N-hydroxyamide, N-hydroxythioamide, hydroxyurea, and N-hydroxythiourea derivatives of selected nsaids as antiinflammatory agents

ABSTRACT

The present invention includes N-hydroxyamide, N-hydroxyurea, N-hydroxythioamide, and N-hydroxythiourea derivatives of fenamates, indomethacin, cicloprofen, oxepinac, and indoprofen as dual inhibitors or selective inhibitors of cyclooxygenase and 5-lipoxygenase.

BACKGROUND OF THE INVENTION

The present invention is novel compounds which are N-hydroxyamide,N-hydroxyurea, N-hydroxythioamide and N-hydroxythiourea derivatives offenamate, indomethacin, cycloprofen, oxapinac and indoprofen, andpharmaceutically acceptable acid addition or base salts thereof,pharmaceutical compositions and methods of use therefor. The inventioncompounds are now found to have activity as dual inhibitors or selectiveinhibitors of 5-lipoxygenase and cyclooxygenase providing treatment ofconditions advantageously affected by such inhibition includinginflammation, arthritis, pain, fever, and the like. Thus, the presentinvention is also a pharmaceutical composition or method of usetherefor.

Specific hydroxamates of fenamic acid are shown in copending U.S.application Ser. No. 134,725 which includes a reference to EuropeanApplication Publication No. 0,196,184 having broad disclosure ofhydroxamic acid derivatives of selected aryl ring systems effective ashigh potency inhibitors of 5-lipoxygenase. Summers et al also disclosedhydroxamic acid inhibitors of 5-lipoxygenase in an abstract, September,1987 and J. Med. Chem., 1987, 30, 574-80. Indole, benzofuran andbenzothiophine each having an --A--N--C--R₁ substituent is disclosed inEuropean Application Publication No. 0279,263. Additionally various ringsystems are known which are attached to a similar N--C containingsubstituent. For example, a (phenylalkoxy) phenyl; a biphenyl alkyl; aphenyl or naphthyl; 7-oxabicyclo (2.2.2) heptane; dibenzofuran; and(alkoxy) or (phenyloxy)-phenyl and naphthyl or thiofurane are disclosedin European Application Publication No. 279,281, British No. 2,191,194,PCT Application No. GB 86/00791, British No. 2,194,531, U.S. Pat. No.4,769,387, and European Application Publication No. 292,699respectively. European Application Publication No. 196,674 alsodiscloses compounds including an --N--C-- containing moiety havingphenyl, naphthyl or sulfur heterocyclic ring systems attached directlyor through various linking groups to the N of the moiety. The J. Org.Chem. 1989, 54, 1221-1223 and J. Med. Chem., 31, 1, pp. 3-5 (January1988) disclose (hydroxy) or (phenylalkoxy)-phenyl, naphthyl andphenoxyphenyl rings in like manner attached to an --N--C-- containingsubstituent.

However, none of the above noted disclosures describe hydroxamates ofthe configuration disclosed in this application on the selectednonsteroidal antiinflammatory type substrates.

Thus, the differences between the present invention and the teachings ofthe references are readily apparent.

SUMMARY OF THE INVENTION

The present invention is a compound of the formula (I) ##STR1## and apharmaceutically acceptable acid addition or base salt thereof; whereinAr is ##STR2## wherein R₁, R₂ and R₃ are independently H, fluoro,chloro, bromo, iodo, CF₃, lower alkyl, CN, hydroxy, lower alkoxy,--S(0)_(q) -lower alkyl, NO₂, or NR₄ R₅ wherein R₄ or R₅ areindependently H, lower alkyl or acyl and q is an integer of 0, 1 or 2;##STR3## Y is O or S; W is alkyl, aryl, aralkyl, 0-alkyl NR₆ R₇,

(CH₂)_(n) CO₂ R₇, NH(CH₂)_(m) CO₂ R₇, NH(CH₂)_(p) NR₆ R₇, NHCH₂ CH═CH2

wherein

(i) R₆ and R₇ are independently H or lower alkyl,

(ii) n is 0 to 3 except that Y cannot be S when n is 0,

(iii) m is 0 to 3, and

(iv) p is 2 to 3.

Additionally, the present invention is for novel compounds of theformula (II and IIa).

    N-Hydroxy-9H-fluorene-2-methanamine                        II,

    N-Hydroxy-alpha-methyl-9H-fluorene-2-methanamine           IIa

and the pharmaceutically acceptable acid addition or base salt of each.

The compounds of formula II and IIa are useful as intermediates in aprocess for the preparation of selected compounds of the formula I andalso each is active as a dual inhibitor or selective inhibitor of5-lipoxygenase and cyclooxygenase.

The present invention is also a pharmaceutical composition for thetreatment of a condition advantageously affected by the dual inhibitionor selective inhibition of 5-lipoxygenase and cyclooxygenase whichcomprises an amount effective for the treatment of the conditioncomprising a compound of the formula I and the pharmaceuticallyacceptable acid addition or base salt thereof or a compound of theformula II, IIa and the pharmaceutically acceptable salts of each,together with a pharmaceutically acceptable carrier. The "condition" ismeant to include, for example, inflammation, arthritis or otherinflammatory diseases, allergies, pain, fever, and psoriasis, butpreferably inflammation.

The present invention is also a method for treatment of the condition asnoted above in mammals, including humans, suffering therefrom with acompound of the formula I or the pharmaceutically acceptable acidaddition or base salt thereof, or a compound of the formula II or IIaand the pharmaceutically acceptable salt thereof, in unit dosage form.The invention also provides for use of any such compound of formula I orsalt thereof or of formula II or IIa or salt thereof in the manufactureof medical therapeutical agent.

Pharmaceutical composition or use of the compound or salt of formula Ior of the compound or salt of formula II or IIa is meant to includetreatment understood to be prophylactic pertinent to the foregoing namedcondition.

The preferred compounds of the present invention are of the formula Iand in the present invention include:N-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methyl]-N-hydroxyacetamide

N-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methyl]-N-hydroxyacetamide,monosodium salt

N-hydroxy-N-[[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]methyl]acetamide

N-hydroxy-N-[[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]methyl]acetamide,monosodium salt

1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-[(methylamino)thioxomethyl]-1H-indole-3methanamine

N-hydroxy-N'-methyl-N-[[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]methyl]urea

N-[(6,11-dihydro-11-oxodibenz[b,e]oxepin-3-yl)methyl]-N-hydroxy-2-methylpropanamide

N-hydroxy-N-[[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]methyl]carbamicacid, ethyl ester

N-[1-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]ethyl]-N-hydroxyacetamide.

The most preferred compound of formula I in the present invention isN-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methyl]-N-hydroxyacetamide.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of formula (I) the term "lower alkyl" includes an alkylgroup of from one to six carbons such as methyl, ethyl, propyl, butyl,and the like and isomers thereof. Halogen is chloro, bromo or fluoro.Further, the term "lower alkoxy" is of from one to six carbons such asmethoxy, ethoxy, propoxy, butoxy and the like and isomers thereof.Likewise, acyl is of from two to six carbons incuding acetyl, propionyl,butyryl, and the like and isomers thereof.

Me is methyl, Et is ethyl and iPr is isopropyl.

Aryl is phenyl unsubstituted or substituted by halo, nitro, cyano, loweralkyl, lower alkoxy or trifluoromethyl.

Aralkyl is an aryl as defined above attached through an alkylenyl offrom one to four carbons.

Appropriate compounds of formula I or II and IIA are useful in the freebase form, in the form of base salts where possible, and in the form ofacid addition salts. The three forms are within the scope of theinvention. In practice, use of the salt form amounts to use of the baseform. Pharmaceutically acceptable salts within the scope of theinvention may be those derived from mineral acids such as hydrochloricacid and sulfuric acid; and organic acids such as ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, and the like, giving thehydrochloride, sulfate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and the like, respectively, or those derived frombases such as suitable organic and inorganic bases. Examples ofpharmaceutically acceptable base addition salts with compounds of thepresent invention include organic bases which are nontoxic and strongenough to form such salts. These organic bases form a class whose limitsare readily understood by those skilled in the art. Merely for purposesof illustration, the class may be said to include mono-, di-, andtrialkylamines such as methylamine, dimethylamine, and triethylamine;mono-, di-, or trihydroxyalkylamines such as mono-, di-, ortriethanolamine; amino acids such as arginine and lysine; guanidine;N-methylglucosamine; N-methylglucamine; L-glutamine; N-methylpiperazine;morpholine; ethylenediamine; N-benzylphenethylamine; tris(hydroxymethyl)aminomethane; and the like. (See for example, "Pharmaceutical Salts," J.Pharm. Sci., 66(1):1-19 (1977).) Salts of inorganic bases includesodium, potassium, calcium or the like.

The acid addition salts of said basic compounds are prepared either bydissolving the free base or acid of compound I or II and IIa in aqueousor aqueous alcohol solution or other suitable solvents containing theappropriate acid or base and isolating the salt by evaporating thesolution, or by reacting the free base of compound I or II and IIa withan acid as well as reacting compound I having an acid group thereon witha base such that the reactions are in an organic solvent, in which casethe salt separates directly or can be obtained by concentration of thesolution. Salts can also be prepared by adding base to an aqueousalcohol solution of another salt.

The compounds of the invention may contain geometric isomers. Thus, theinvention includes the individual isomers and mixtures thereof. Theindividual isomers may be prepared or isolated by methods known in theart.

In determining when a lipoxygenase, cyclooxygenase, or duallipoxygenase/cyclooxygenase inhibitor is indicated, of course interalia, the particular condition in question and its severity, as well asthe age, sex, weight, and the like of the subject to be treated, must betaken into consideration and this determination is within the skill ofthe attendant physician.

For medical use, the amount required of a compound of formula I orpharmacologically acceptable salt thereof or II and IIa orpharmacologically acceptable salt thereof to achieve a therapeuticeffect will, of course, vary both with the particular compound, theroute of administration, the mammal under treatment, and the particulardisorder or disease concerned. A suitable dose of a compound of formulaI or pharmacologically acceptable salt thereof or II and IIa orpharmacologically acceptable salt thereof for a mammal suffering from,or likely to suffer from any condition as described hereinbefore is 0.1μg-500 mg of the compound per kilogram body weight per day. In the caseof systemic administration, the dose may be in the range of 0.5 to 500mg of the compound per kilogram body weight, the most preferred dosagebeing 0.5 to 50 mg/kg of mammal body weight administered two or threetimes daily. In the case of topical administration, e.g., to the skin oreye, a suitable dose may be in the range 0.1 ng-100 μg of the compoundper kilogram, typically about 0.1 μg/kg.

In the case of oral dosing for the treatment or prophylaxis of arthritisor inflammation in general, due to any course, a suitable dose of acompound of formula I or II and IIa or physiologically acceptable saltthereof, may be as specified in the preceding paragraph, but mostpreferably is from 1 mg to 10 mg of the compound per kilogram, the mostpreferred dosage being from 1 mg to 5 mg/kg of mammal body weight, forexample from 1 to 2 mg/kg.

It is understood that the ordinarily skilled physician or veterinarianwill readily determine and prescribe the effective amount of thecompound to prevent or arrest the progress of the condition for whichtreatment is administered. In so proceeding, the physician orveterinarian could employ relatively low doses at first, subsequentlyincreasing the dose until a maximum response is obtained.

While it is possible for an active ingredient to be administered alone,it is preferable to present it as a pharmaceutical formulationcomprising a compound of formula I or II and IIa or a pharmacologicallyacceptable acid addition or base salt thereof and a pharmacologicallyacceptable carrier therefor. Such formulations constitute a furtherfeature of the present invention.

The formulations, both for veterinary and for human medical use, of thepresent invention comprise an active ingredient in association with apharmaceutically acceptable carrier therefor and optionally othertherapeutic ingredient(s). The carrier(s) must be `acceptable` in thesense of being compatible with the other ingredients of the formulationsand not deleterious to the recipient thereof.

The formulations include those in a form suitable for oral, pulmonary,ophthalmic, rectal, parenteral (including subcutaneous, intramuscular,and intravenous), intraarticular, topical, nasal, or buccaladministration. Such formulations are understood to include long-actingformulations known in the art.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well-known in the art of pharmacy.All methods may include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing the active ingredient into association with a liquidcarrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administrationmay be in the form of discrete units such as capsules, cachets, tablets,or lozenges, each containing a predetermined amount of the activeingredient; in the form of a powder or granules; in the form of asolution or a suspension in an aqueous liquid or nonaqueous liquid; orin the form of an oil-in-water emulsion or a water-in-oil emulsion. Theactive ingredient may also be in the form of a bolus, electuary, orpaste.

The usefulness of the compounds of the present invention as inhibitorsof the 5-lipoxygenase enzyme, cyclooxygenase, or in treating relateddiseases or conditions may be demonstrated by their effectiveness invarious standard test procedures. A description of each procedurefollows.

ARBL/ARBC Whole Cell 5-Lipoxygenase and Cyclooxygenase Assays

Materials

The rat basophilic leukemia cell line (RBL-1) was obtained from theAmerican Type Culture Collection (Rockville, Md.).

Radioimmunoassay (RIA) kits of LTB₄ and PGF₂α were obtained fromAmersham (Arlington Heights, Ill.) and Seragen (Boston, Mass.),respectively.

All tissue culture media were obtained from GIBCO (Grand Island, N.Y.).

Method

RBL-1 cells are grown in suspension culture in Eagle's minimum essentialmedium supplemented with 12% fetal bovine serum at 37° C. in anincubator supplied with air-5% carbon dioxide. Cells are harvested bycentrifugation. They are washed with cold phosphate buffered saline pH7.4 (PBS; NaCl, 7.1 g; Na₂ HPO₄, 1.15 g; KH₂ PO₄, 0.2 g; and KCl, 0.2g/l). Cells are finally suspended in PBS containing 1.0 mM calcium at adensity of 2×10⁶ cells/ml. Cells are incubated with and without testagent (in DMSO) (1% DMSO is without effect on arachidonic acidmetabolism) for ten minutes at room temperature. Calcium ionophoreA23187 (5 μM) is added and cells are incubated for seven minutes at 37°C. The reaction is stopped by chilling the tubes on ice for ten minutes.Cells are separated by centrifugation and the supernatant is stored at-20° C. Aliquots (100 μl) are analyzed for LTB₄ and PGF₂α usingradioimmunoassay kits as provided by the supplier.

Tables 1-4 contain biochemical data obtained from this whole cell assayeither as IC₅₀ s which are calculated as the amount of test compoundcausing 50% inhibition of LTB₄ or PGF₂α formation or % inhibition ofLTB₄ or PGF₂α at the indicated amount expressed as μM.

                  TABLE 1                                                         ______________________________________                                         ##STR4##                                                                                      ARBL      ARBC                                                                IC.sub.50 (μM)                                                                       IC.sub.50 (μM)                                  Example C(Y)W      R       or % Inhibitors @ μM                            ______________________________________                                        1       H          H        97% @ 16.sup.a                                                                         76% @ 16.sup.b                           3       C(O)COOH   H       N.sup.c   N.sup.c                                  4       C(O)Me     H       100% @ 16.sup.a                                                                         12                                       2       C(O)COOEt  H        96% @ 16.sup.a                                                                         N.sup.c                                  5       C(O)iPr    H        99% @ 16.sup.a                                                                         N.sup.c                                  6       C(O)NHMe   H       100% @ 16.sup.a                                                                         N.sup.c                                  7       H          Me      100% @ 16.sup.a                                                                         89% @ 16.sup.b                           8       C(O)NHMe   Me      0.91      N.sup.c                                  9       C(O)NHEt   Me      100% @ 16.sup.a                                                                         49% @ 16.sup.b                           11      C(O)Me     Me      0.76      N.sup.c                                  10      C(S)NHMe   Me      100% @ 16.sup.a                                                                         59% @ 16.sup.b                           12      C(O)OEt    Me       95% @ 16.sup.a                                                                         79% @ 16.sup. b                          13      C(O)i-Pr   Me       90% @ 16.sup.a                                                                         N.sup.c                                  14      C(S)NHEt   Me        56% @ 0.25.sup.a                                                                      N.sup.c                                  ______________________________________                                         .sup.a % inhibition of LTB.sub.4 at 16 μM or 0.25 μM.                   .sup.b % inhibition of PGF.sub.2α at 16 μM.                          .sup.c Less than 40% inhibition at 16 μM.                             

                  TABLE 2                                                         ______________________________________                                         ##STR5##                                                                                      ARBL      ARBC                                                                IC.sub.50 (μM)                                                                       IC.sub.50 (μM)                                  Example                                                                              X        C(Y)W      or % inhibition @ μM                            ______________________________________                                        20     CH.sub.2                                                                                ##STR6##  0.51      N.sup.c                                  18     CH.sub.2                                                                                ##STR7##  0.84      N.sup.c                                  19     CH.sub.2                                                                                ##STR8##   84% @ 16.sup.a                                                                         N.sup.c                                  17     CH.sub.2                                                                                ##STR9##  100% @ 16.sup.a                                                                         5.8                                      ______________________________________                                         .sup.a % inhibition of LTB.sub.4 at 16 μM.                                 .sup.c Less than 40% inhibition at 16 μM.                             

                  TABLE 3                                                         ______________________________________                                         ##STR10##                                                                                            ARBL       ARBC                                       Exam-                   IC.sub.50 (μM)                                                                        IC.sub.50 (μM)                          ple   R      R.sub.1 /R.sub.2                                                                         W     or % inhibition @ μM                         ______________________________________                                        54    H      2,6-diCl,3-Me                                                                            Me    0.18     5.0                                    53    Me     2,6-diCl,3-Me                                                                            Me    1.8      N @ 32.sup.c                           47    H      2,3-diMe   Me    0.51     15                                     55    H      3-CF.sub.3 Me    0.28     5.2                                    48    H      2,6-diCl   Me    1.3      N @ 32.sup.c                           56    H      3-CF.sub.3 NHMe  0.12     2.2                                    57    H      3-CF.sub.3 OEt   100% @ 16.sup.a                                                                        91% @ 16.sup.b                         ______________________________________                                         .sup.a % inhibition of LTB.sub.4 at 16 μM.                                 .sup.b % inhibition of PGF.sub.2α at 16 μM.                          .sup.c Less than 40% inhibition at 32 μM.                             

                  TABLE 4                                                         ______________________________________                                         ##STR11##                                                                                      ARBL     ARBC                                                                 IC.sub.50 (μM)                                                                      IC.sub.50 (μM)                                  Example                                                                              Y      W             or % inhibition @ μM                           ______________________________________                                        63     O      Me            1.4      15                                       64     O      CH.sub.2 COOEt                                                                              1.1      14                                       69     O      NHMe          2.5      N.sup.c                                  65     O      (CH.sub.2).sub.2 COOMe                                                                      1.3      9.4                                      67     O      OMe            97% @ 32.sup.a                                                                        16                                       74     S      NHMe           0.40    7.1                                      68     O      NH.sub.2       98% @ 16.sup.a                                                                        N.sup.c                                  66     O      (CH.sub.2).sub.2 COOH                                                                       N @ 16.sup.c                                                                           N.sup.c                                  72     O      NHCOOEt        98% @ 16.sup.a                                                                        N.sup.c                                  73     O      NHCH.sub.2 CO.sub.2 Et                                                                      100% @ 16.sup.a                                                                        N.sup.c                                  71     O      NHCH.sub.2 CHCH.sub.2                                                                       100% @  16.sup.a                                                                       50% @ 16.sup.b                           70     O      NMe.sub.2     100% @ 16.sup.a                                                                        73% @ 16.sup.b                           ______________________________________                                         .sup.a % inhibition of LTB.sub.4 at 16 μM.                                 .sup.b % inhibition of PGF.sub.2 at 16 μM.                                 .sup.c Less than 40% inhibition.                                         

Accordingly, the present invention is for a compound of the formula I,II or IIa or pharmaceutically acceptable salts thereof, and apharmaceutical composition or method of use, therefor, having usefulnessin treating conditions advantageously inhibiting 5-lipoxygenase orcyclooxygenase such as outlined above.

In addition to the compounds of formula I or II and IIa, thepharmaceutical compositions can also contain other active ingredients,such as cyclooxygenase inhibitors, nonsteroidal antiinflammatory drugs(NSAIDS), peripheral analgesic agents such as zomepirac, diflunisal, andthe like. The weight ratio of the compound of the formula I or II andIIa to the second active ingredient may be varied and will depend uponthe effective dose of each ingredient. Generally, an effective dose ofeach will be used. Thus, for example, when a compound of the formula Ior II and IIa is combined with an NSAID, the weight ratio of thecompound of the formula I or II and IIa to the NSAID will generallyrange from about 1000:1 to about 1:1000, preferably about 200:1 to about1:200. Combinations of a compound of the formula I or II and IIa andother active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

Combinations of a compound of the formula I and other active ingredientswill generally be in the aforementioned ratios.

NSAIDS can be characterized into five groups:

(1) the propionic acid derivatives;

(2) the acetic acid derivatives;

(3) the fenamic acid derivatives;

(4) the biphenylcarboxylic acid derivatives; and

(5) the oxicams or a pharmaceutically acceptable salt thereof.

The propionic acid derivatives which may be used comprise: ibuprofen,ibuprofen aluminum, indoprofen, ketoprofen, naproxen, benoxaprofen,flurbiprofen, fenoprofen, fenbufen, pirprofen, carprofen, oxaprozin,pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofen,fluprofen, and bucloxic acid. Structurally related propionic acidderivatives having similar analgesic and antiinflammatory properties arealso intended to be included in this group.

Thus, "propionic acid derivatives" as defined herein are nonnarcoticanalgesics/nonsteroidal antiinflammatory drugs having a free--CH(CH₃)COOH or --CH₂ CH₂ COOH group (which optionally can be in theform of a pharmaceutically acceptable salt group, e.g., --CH(CH₃)COO⁻Na⁺ or --CH₂ CH₂ COO⁻ Na⁺), typically attached directly or via acarbonyl function to a ring system, preferably to an aromatic ringsystem.

The acetic acid derivatives which may be used comprise: indomethacin,which is a preferred NSAID, sulindac, tolmetin, zomepirac, diclofenac,fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac,zidometacin, acematacin, fentiazac, clidanac, oxpinac, and fenclozicacid. Structurally related acetic acid derivatives having similaranalgesic and antiinflammatory properties are also intended to beencompassed by this group.

Thus, "acetic acid derivatives" as defined herein are nonnarcoticanalgesics/nonsteroidal antiinflammatory drugs having a free --CH₂ COOHgroup (which optionally can be in the form of a pharmaceuticallyacceptable salt group, e.g. --CH₂ COO⁻ Na⁺), typically attached directlyto a ring system, preferably to an aromatic or heteroaromatic ringsystem.

The fenamic acid derivatives which may be used comprise: mefanamic acid,meclofenamic acid, flufenamic acid, niflumic acid, and tolfenamic acid.Structurally related fenamic acid derivatives having similar analgesicand antiinflammatory properties are also intended to be encompassed bythis group.

Thus, "fenamic acid derivatives" as defined herein are nonnarcoticanalgesics/nonsteroidal antiinflammatory drugs which contain the basicstructure: ##STR12## which can bear a variety of substituents and inwhich the free --COOH group can be in the form of a pharmaceuticallyacceptable salt group, e.g., --COO⁻ Na⁺.

The biphenylcarboxylic acid derivatives which can be used comprise:diflunisal and flufenisal. Structurally related biphenylcarboxylic acidderivatives having similar analgesic and antiinflammatory properties arealso intended to be encompassed by this group.

Thus, "biphenylcarboxylic acid derivatives" as defined herein arenonnarcotic analgesics/nonsteroidal antiinflammatory drugs which containthe basic structure: ##STR13## which can bear a variety of substituentsand in which the free --COOH group can be in the form of apharmaceutically acceptable salt group, e.g., --COO--Na⁺.

The oxicams which can be used in the present invention comprise:piroxicam, sudoxicam, isoxicam, and 4-hydroxy-1,2-benzothiazine1,1-dioxide 4-(N-phenyl)-carboxamide. Structurally related oxicamshaving similar analgesic and antiinflammatory properties are alsointended to be encompassed by this group.

Thus, "oxicams" as defined herein are nonnarcoticanalgesics/nonsteroidal antiinflammatory drugs wich have the generalformula: ##STR14## wherein R is an aryl or heteroaryl ring system.

The following NSAIDS may also be used: acemetacin, alminoprofen, amfenacsodium, aminoprofen, anitrazafen, antrafenine, auranofin, bendazaclysinate, benzydamine, beprozin, broperamole, bufezolac, carprofen,cinmetacin, ciproquazone, clidanac, cloximate, dazidamine, deboxamet,delmetacin, detomidine, dexindoprofen, diacerein, di-fisalamine,difenpyramide, emorfazone, enfenamic acid, enolicam, epirizole,etersalate, etodolac, etofenamate, fanetizole mesylate, fenclofenac,fenclorac, fendosal, fenflumizole, fentiazac, feprazone, floctafenine,flunixin, flunoxaprofen, fluproquazone, fopirtoline, fosfosal,furcloprofen, furofenac, glucametacin, guaimesal, ibuproxam, isofezolac,isonixin, isoprofen, isoxepac, isoxicam, lefetamine HCl, leflunomide,lofemizole, lonazolac calcium, lotifazole, loxoprofen, lysin,clonixinate, meclofenamate sodium, meseclazone, microprofen, nabumetone,nictindole, nimesulide, orpanoxin, oxametacin, oxapadol, oxaprozin,perisoxal citrate, pimeprofen, pimetacin, piproxen, pirazolac,pirfenidone, pirprofen, pranoprofen, proglumetacin maleate, proquazone,pyridoxiprofen, sudoxicam, suprofen, talmetacin, talniflumate,tenoxicam, thiazolinobutazone, thielavin B, tiaprofenic acid, tiaramideHCl, tiflamizole, timegadine, tioxaprofen, tolfenamic acid, tolpadol,tryptamid, ufenamate, and zidometacin.

Finally, NSAIDS which may also be used include the salicylates,specifically aspirin, and the phenylbutazones, and pharmaceuticallyacceptable salts thereof.

Pharmaceutical compositions comprising the formula I or II and IIacompounds may also contain as the second active ingredient,antihistaminic agents such as benadryl, dramamine, histadyl, phenergan,and the like. Alternatively, they may include prostaglandin antagonistssuch as those disclosed in European Patent Application No. 11,067 orthromboxane antagonists such as those disclosed in U.S. Pat. No.4,237,160. They may also contain histidine decarboxylase inhibitors suchas α-fluoromethylhistidine, described in U.S. Pat. No. 4,325,961. Thecompounds of the formula I may also be advantageously combined with anH₁ or H₂ -receptor antagonist, such as for instance cimetidine,ranitidine, terfenadine, famotidine, temelastine, acrivastine,loratadine, cetrizine, tazifylline, azelastine, aminothiadiazolesdisclosed in EP No. 81102976.8 and like compounds, such as thosedisclosed in U.S. Pat. Nos. 4,283,408; 4,362,736; 4,394,508, andEuropean Patent Application No. 40,696. The pharmaceutical compositionsmay also contain a K⁺ /H⁺ ATPase inhibitor such as omeprazole, disclosedin U.S. Pat. No. 4,255,431, and the like. Each of the referencesreferred to in this paragraph is hereby incorporated herein byreference.

The compound of the formula I and their salts may be prepared generallyby the following processes.

The Scheme A provides a general method of preparation as follows:##STR15##

Generally, the reactions shown in Scheme A can be described as follows:

The oximes IX can be prepared from the aldehydes VIII(R═H) or ketonesVIII(R═CH₃) by reacting with hydroxylamine.HCl in methanol or ethanoland sodium acetate at about -10° C. to reflux temperature for one hourto 48 hours depending on the nature of the carbonyl compound readilyunderstood by an ordinarily skilled artisan. The oxime can also beprepared by reacting the carbonyl compound with NH₂ OH.HCl in pyridineat about 20° C. to reflux temperature for 1.0 hour to 18 hours.

Reduction of the oxime IX is carried out with Na(CN)BH₃ in acetic acidat about -5° C. to 40° C. for 1.0 hour to 18 hours. The Na(CN)BH₃reduction can also be carried out in methanol/HCl at about 0° C. to 35°C. for 2.0 hours to 24 hours. Borane pyridine complex in ethanol ormethanol and dilute HCl can also be used for the reduction of oximes IXat about 10° C. to 40° C. for 2.0 hours to 24 hours.

The hydroxylamines III are acylated with an acid chloride, such as##STR16## and NaOAc in dioxane/water at about -5° C. to 30° C. for 30minutes to 24 hours. Alternatively they can be acylated with an acidchloride such as ##STR17## in CH₂ Cl₂ in presence of an organic basesuch as triethylamine or diisopropylethylamine at about 10° C. to 35° C.but preferably at room temperature. In the latter case N-, O-diacylatedproduct is formed which is hydrolyzed with aqueous inorganic base suchas lithium hydroxide in an alcohol solvent at about 20° C. to refluxtemperature preferably at room temperature for 30 minutes to 8 hours togive the N-acylated product V.

The hydroxyureas IV(Y═O) and hydroxythioureas IV(Y═S) are prepared fromthe hydroxylamines III by reacting with the corresponding isocyanates orisothiocyanates in organic solvents such as toluene or toluene/THFmixture or toluene/DMF mixture at about 10° C. to about 40° C. for 2.0hours to 24 hours, or in dioxane/water at about 0° C. to about 24° C.for two to 24 hours.

The hydroxylamines III can also be prepared by alkylation of O-protectedhydroxylamine, followed by deprotection. That is, the alcohol VI isconverted to its halo derivative. Then the halo derivative can bereacted with 1-5 equivalents of O-tetrahydropyranylhydroxylamine orO-trimethylsilylhydroxylamine in an organic solvent such as DMF orchloroform at about 20° C. to about 60° C. for one to 24 hours.Deprotection can be done under acidic conditions such as methanolic HClat about 0° C., to reflux temperature for 15 minutes to 24 hours, orpyridinium p-toluenesulfonate in an alcohol solvent at about 0° C. to60° C. for 15 minutes to three hours.

The intermediate O-THP-hydroxylamines VII alternatively may be reactedwith the acid chloride, i.e. ##STR18## or isocyanate R'--N═C═O orisothiocyanate R'--N═C═S according to the method described above for theO-unprotected hydroxylamines with the acid catalyzed deprotectionfollowing acylation.

Scheme 1 below shows a novel method of preparing starting compoundswherein Ar is ##STR19##

In Scheme 1, N-Substituted phenyl-1H-isoindol-1-one VIII' is prepared byreacting ortho-phthalic dicarboxaldehyde with the correspondingsubstituted phenylisocyanate at an elevated temperature preferably at170°-180° C. without any solvent for 3 to 6 hours.

The acetophenone VIII' derivative is converted to the correspondingoxime by reacting with hydroxylamine HCl in pyridine at elevatedtemperature preferably at 100°-110° C. for 2 to 8 hours. This latterconversion of the acetophenone VIII' to the oxime is as shown in SchemeA. ##STR20##

The preferred process to prepare intermediate ketones VIII of Scheme Ain the fenamate series is shown as VIII" in Scheme 2 above. Reaction ofthe ester with dimsyl anion ##STR21## is followed by reduction of theintermediate β-ketosulfoxide with aluminum amalgam. Conditions arewithin the skill of an ordinary artisan. Conversion of the ketone to thecompounds of formula I is as previously discussed for Scheme A.##STR22##

The preferred method for preparing oximes IX of Scheme A in theindomethacin series IX' is shown in Scheme 3 above. Reaction of themethyl ketone with O-tetrahydropyranylhydroxylamine followed byacylation of the indole nitrogen with p-chlorobenzoyl chloride/sodiumhydride and removal of the THP group with acid gives intermediate theoxime IX'. The oxime IX' is converted to compounds of formula I aspreviously discussed for Scheme A.

One of skill in the art would recognize variations in the sequence andwould recognize appropriate reaction conditions from analogous reactionswhich may be appropriately used in the processes to make the compound offormula (I) herein. Further, the starting materials are known or can beprepared by known methods.

Under certain circumstances as discussed above, it is necessary toprotect either the N or O of intermediates. The examples above showingthis noted process with suitable protecting groups which are known arenot meant to be limiting. Introduction and removal of such suitableoxygen and nitrogen protecting groups are well-known in the art oforganic chemistry; see for example "Protective Groups in OrganicChemistry," J. F. W. McOmie, Advances in Organic Chemistry, Vol. 3,191-281 (1963); R. A. Borssonas, Advances in Organic Chemistry, Vol. 3,159-190 (1963); J. F. W. McOmie, Chem. & Ind., 603 (1979), and T. W.Greene, "Protective Groups in Organic Synthesis", Wiley (New York) 1981,Chapters 2, 3, and 7.

Examples of suitable oxygen protecting groups are benzyl,t-butyldimethylsilyl, ethoxyethyl, methoxyethoxymethyl, and the like.Protection of an N-H containing moiety is necessary for some of theprocesses described herein for the preparation of compounds of thisinvention. Suitable nitrogen protecting groups are benzyl,triphenylmethyl, trialkylsilyl, trichloroethylcarbamate,trichloroethoxycarbonyl, vinyloxycarbamate acetyl, and the like.

Under certain circumstances it is necessary to protect two differentoxygens with dissimilar protecting groups such that one can beselectively removed while leaving the other in place. The benzyl andt-butyldimethylsilyl groups are used in this way; either is removable inthe presence of the other, benzyl being removed by catalytichydrogenolysis, and t-butyldimethylsilyl being removed by reaction with,for example, tetra-n-butylammonium fluoride.

In the process described herein for the preparation of compounds of thisinvention the requirements for protective groups are generally wellrecognized by one skilled in the art of organic chemistry, andaccordingly the use of appropriate protecting groups is necessarilyimplied by the processes of the charts herein, although not expresslyillustrated.

The products of the reactions described herein are isolated byconventional means such as extraction, distillation, chromatography, andthe like.

The invention is further elaborated by the representative examples asfollows. Such examples are not meant to be limiting.

EXAMPLE 1 N-Hydroxy-9H-fluorene-2-methanamine

A solution of 2-fluorenecarboxaldehyde (26.23 g, 0.135 mol),hydroxylamine.HCl (31.2 g, 0.45 mol), and NaOAc (41.0 g, 0.50 mol) inmethanol (250 mL) is stirred at 24° C. for 18 hours. The reactionmixture is filtered off from NaCl and the filtrate concentrated todryness. The residue is extracted with CH₂ Cl₂. The pooled extract iswashed with water, dried (Na₂ SO₄), and concentrated under reducedpressure to afford the oxime as a white solid. The crude oxime isrecrystallized from n-hexane-CH₂ Cl₂ to give analytically pure solid.Yield 21.2 g (75%); mp 158°-160° C. A solution of the oxime (4.2 g, 0.02mol) in acetic acid (60 ml) is slowly treated with Na(CN)BH₃ (6.0 g,0.096 mol) under nitrogen atmosphere. After the addition is complete thereaction mixture is stirred at 24° C. for 3.0 hours and then poured ontoice and NaOH solution to attain pH 14.0. The product is extracted withCH₂ Cl₂. The organic layer is washed with water and brine, and thendried over Na₂ SO₄. Removal of solvent gives an oil which is allowed tocrystallize from a small amount of CH₂ Cl₂ to give white crystallineN-hydroxy-9H-fluorene-2-methanamine. Yield 2.6 g (61.5%); mp 150°-152°C.

Anal. Calcd for C₁₄ H₁₃ NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.35;H, 6.15; N, 6.57.

EXAMPLE 2 (9H-Fluoren-2-ylmethyl)hydroxyamino-oxo-acetic acid, ethylester

The crude hydroxylamine (4.2 g, 0.02 mol) from Example 1 is dissolved indioxane (80 ml) and water (50 ml). The turbid solution is cooled to -5°C. and then treated with NaOAc (3.3 g, 0.04 mol) followed by ethyloxalylchloride (3.0 g, 0.022 mol). The mixture is stirred at 24° C. for3.0 hours, poured onto ice-1N HCl (40 mL) and extracted with CH₂ Cl₂.The extract is washed with brine, water and dried over Na₂ SO₄. Thesolvent is distilled off to give(9H-fluoren-2-ylmethyl)hydroxyamino-oxo-acetic acid, ethyl ester whichis fractionally recrystallized from isopropyl ether and CH₂ Cl₂ and thenfrom isopropyl ether. Yield 1.6 g (26%); mp 130°-131° C.

Anal. Calcd for C₁₈ H₁₇ NO₄ : C, 69.44; H, 5.50; N, 4.50 Found: C,69.72; H, 5.53; N, 4.39.

EXAMPLE 3 (9H-Fluoren-2-ylmethyl)hydroxyamino-oxo-acetic acid

The crude ester (1.9 g, 6 mmol) from Example 2 is dissolved in ethanol(30 ml) and water (30 ml) and then treated with 1N NaOH solution (12.2ml, 12 mmol). The mixture is stirred at room temperature for 15 minutesand then warmed on a steam bath for five minutes. The cooled solution isdiluted with water (300 ml), filtered and then acidified with 1N HCl topH 1.0 when (9H-fluoren-2-ylmethyl) hydroxyamino-oxo-acetic acidprecipitated out. The crude product is triturated with methanol and CH₂Cl₂ to give the analytical product. Yield 0.42 g (22%); mp >260° C.

Anal. Calcd for C₁₆ H₁₃ NO₄.2H₂ O: C, 60.18; H, 5.37; N, 4.39. Found: C,60.54; H, 3.91; N, 4.31.

EXAMPLE 4 N-(9H-Fluoren-2-ylmethyl)-N-hydroxy-acetamide

The crude hydroxylamine (4.2 g, 0.02 mol) from Example 1 is dissolved indioxane (100 ml) and water (50 ml) and cooled to -5° C. The cooledsolution is treated with sodium acetate (3.3 g, 0.04 mol) and acetylchloride (1.75 g, 0.022 mol) and the resulting mixture is stirred at 24°C. for 30 minutes and poured onto ice and dilute HCl whenN-(9H-fluoren-2-ylmethyl)-N-hydroxy-acetamide precipitated out. Thecrude product is filtered, washed and dried and then recrystallized fromTHF and isopropyl ether. Yield 35 3.3 g (65%); mp 182°-183° C. Anal.Calcd for C₁₆ H₁₅ NO₂ : C, 75.87; H, 5.97; N, 5.53 Found: C, 75.79; H,5.76; N, 5.60.

EXAMPLE 5 N-(9H-Fluoren-2-ylmethyl)-N-hydroxy-2-methylpropanamide

Using the method in Example 4, N-hydroxy-9H-fluroene-2-methanamine isreacted with isobutyryl chloride to giveN-(9H-fluoren-2-ylmethyl)-N-hydroxy-2-methyl-propanamide as whitecrystalline solid. Yield 3.5 g (62%); mp 163°-166° C. Anal. Calcd forC₁₈ H₁₉ NO₂ : C, 76.84; 6, 6.81; N, 4.98. Found: C, 76.41; H, 6.72; N,4.88, 4.89.

EXAMPLE 6 N-(9H-Fluoren-2-ylmethyl)-N-hydroxy-N'-methylurea

N-Hydroxy-9H-fluorene-2-methanamine (2.16 g, 0.01 mol) from Example 1 isdissolved in a mixture of toluene (120 ml) and DMF (20 ml) and thentreated with methyl isocyanate. The solution is stirred at roomtemperature for 18 hours whenN-(9H-fluoren-2-ylmethyl)-N-hydroxy-N'-methylurea slowly crystallizedout. It is filtered, washed with toluene and dried in vacuo at 65° C.Yield 1.83 g (68%); mp 196°-198° C. (dec).

Anal. Calcd for C₁₆ H₁₆ N₂ O₂ : C, 71.62; H, 6.01; N, 10.44. Found: C,71.39; H, 5.92; N, 10.19.

EXAMPLE 7 N-Hydroxy-α-methyl-9H-fluorene-2-methanamine

2-Acetylfluorene oxime (11.34 g, 0.05 mol) (prepared according to themethod described in J. Med. Chem., 1988, 31, 60) is suspended in aceticacid (75 ml) and is then treated with Na(CN)BH₃ (15.0 g, 0.25 mol)slowly over 10 minutes when a clear solution is formed. The reactionmixture is poured onto ice (500 g), water (300 ml), and 50% NaOHsolution (85 g) and the pH is adjusted to 7.0 with NaHCO₃ solution. Theproduct is extracted with CH₂ Cl₂, washed with water, dried over Na₂ SO₄and evaporated to dryness to give a semisolid residue (16 g).Trituration with CH₂ Cl₂ -isopropylether gives the pureN-hydroxy-α-methyl-9H-fluorene-2-methanamine. Yield 2.34 g (21%); mp144°-147° C. The filtrate is evaporated to give more crude product whichis used in the next step without any further purification.

Anal. Calcd for C₁₅ H₁₅ NO: C, 79.97; H, 6.71; N, 6.22. Found: C, 80.25;H, 6.72; N, 6.21.

EXAMPLE 8 N-(1-(9H-Fluoren-2-yl)ethyl)-N-hydroxy-N'-methylurea

The crude hydroxylamine (3.89 g, 0.017 mol) from Example 7 is dissolvedin toluene (50 ml) and then treated with methyl isocyanate (0.99 g,0.017 mol). The solution is stirred at 24° C. for 72 hours when theproduct slowly crystallized out. It is filtered, washed with toluene,and then washed thoroughly with CH₃ OH, CH₂ Cl₂ and isopropyl ethermixture (5:10:30). The CH₃ H, CH₂ Cl₂ and isopropyl ether mixture(5:10:30) wash is allowed to stand at 24° C. overnight when theanalytically pure N-(1-(9H-fluoren-2-yl)ethyl)-N-hydroxy-N'-methylureaslowly crystallized out. It is dried in vacuo at 78° C. Yield 0.43 g(9.0%); mp 175°-178° C. (dec).

Anal. Calcd for C₁₇ H₁₈ N₂ O₂ : C, 72.32; H, 6.43; N, 9.92. Found: C,72.12; H, 6.46; N, 10.03.

EXAMPLE 9 N'-Ethyl-N-(1-(9H-fluoren-2-yl)ethyl)-N-hydroxyurea

The hydroxylamine from Example 7 is reacted with ethyl isocyanateaccording to the method described in Example 8 to giveN'-ethyl-N-(1-(9H-fluoren-2-yl)ethyl)-N-hydroxyurea. Yield 1.4 g (33%);mp 128°-132° C. (dec).

Anal. Calcd for C₁₈ H₂₀ N₂ O₂.0.75 H₂ O: C, 69.76; H, 6.99; N, 9.04.Found: C, 69.42; H, 6.52; N, 8.96.

EXAMPLE 10 N-(1-(9H-Fluoren-2-yl)ethyl)-N-hydroxy-N'-methylthiourea

The hydroxylamine from Example 7 is reacted with methyl isothioicyanateaccording to the method described in Example 8 to give theN-(1-(9H-fluoren-2-yl)ethyl)-N-hydroxy-N'-methylthiourea. Yield 2.0 g(94.4%); mp 171°-172° C. (dec).

Anal. Calcd for C₁₇ H₁₈ N₂ OS: C, 68.44; H, 6.08; N, 9.39; S, 10.73.Found: C, 68.48; H, 5.75; N, 9.15; S, 11.05.

EXAMPLE 11 N-(1-(9H-Fluoren-2-yl)ethyl)-N-hydroxy-acetamide

The crude hydroxylamine (4.5 g, 0.02 mol) from Example 7 is dissolved indioxane (50 ml) and water (50 ml) and the solution is cooled to 5° C.The solution is then treated with NaOAc (3.3 g, 0.04 mol) and acetylchloride (1.73 g, 0.022 mol) and the mixture stirred at 24° C. for 2.0hours. It is poured onto ice, H₂ O, and 1N HCl (pH 1.0) when the productoiled out. The product is taken up in CH₂ Cl₂, washed with water anddried (Na₂ SO₄). The solvent is evaporated off to give an oil which ontrituration with isopropyl ether gives a solid which is recrystallizedfrom isopropyl ether to giveN-(1-(9H-fluoren-2-yl)ethyl)-N-hydroxy-acetamide. Yield 1.0 g (18%); mp168°-171° C. Anal. Calcd for C₁₇ H₁₇ NO₂.0.20 H₂ O: C, 75.37; H, 6.47;N, 5.17. Found: C, 75.67, 75.38; H, 6.24, 6.67; N, 5.22, 5.53.

EXAMPLE 12 N-Hydroxy-alpha-methyl-9H-fluorene-2-methanamine carbamicacid, ethyl ester

The crude hydroxylamine (10.0 g, 0.044 mol) from Example 7 is reactedwith ethyl chloroformate according to the method described in Example 11to give the title compound which is purified by flash chromatographythrough silica gel to give analyticalN-Hydroxy-alpha-methyl-9H-fluorene-2-methanamine carbamic acid, ethylester. Yield 1.4 g (11%); mp 111°-112° C.

Anal. Calcd for C₁₈ H₁₉ NO₃.0.10H₂ O: C, 72.27; H, 6.47; N, 4.68. Found:C, 72.09; H, 6.15; N, 4.28.

EXAMPLE 13 N-(1-(9H-Fluoren-2-yl)-N-hydroxy-2-methyl-propanamide

The crude hydroxylamine (8.4 g, 0.037 mol) from Example 7 is reactedwith isobutyryl chloride according to the method described in Example 11to give the title compound which is purified by flash chromatographythrough silica gel to give analyticalN-(1-(9H-fluoren-2-yl)-N-hydroxy-2-methylpropanamide. Yield 0.5 g(4.6%); mp 184°-186° C. (dec).

Anal. Calcd for C₁₉ H₂₁ NO₂ : C, 77.26; H, 7.17; N, 4.74. Found: C,76.79; H, 6.95; N, 4.49.

EXAMPLE 14 N-(1-(9H-Fluoren-2-yl)ethyl)-N-hydroxy-N'-ethylthiourea

The crude hydroxylamine from Example 7 is reacted with ethylisothiocyanate according to the method described in Example 8 to giveN-(1-(9H-fluoren-2-yl)ethyl)-N-hydroxy-N'-ethylthiourea. Yield 100 mg(80%); mp 158°-159° C. (dec).

Anal. Calcd for C₁₈ H₂₀ N₂ OS: C, 69.20; H, 6.45; N, 8.97; S, 10.26Found: C, 69.20; H, 6.72; N, 8.96; S, 9.81.

EXAMPLE 15 6,11-Dihydro-11-oxobibenz[b,e]oxepin-3-carboxaldehyde, oxime

A mixture of 6,11-dihydro-11-oxodibenz[b,e]oxepin-3-carboxaldehyde inToshiyuki Yoshioka et al, J. Med. Chem., (1978), 21, 633 (14.95 g, 0.06mol), hydroxylamine hydrochloride (8.7 g, 0.120 mol), sodium acetate(10.25 g, 0.12 mol) in tetrahydrofuran (300 ml) and methanol (50 ml) isstirred at room temperature for 16 hours. After removal of the solventunder reduced pressure, the residue is dissolved in ethyl acetate. Theorganic layer is separated, washed with water, dried and the solvent isremoved to give 15.9 g of a solid mp 170°-172° C. Recrystallization frommethanol gives 11.63 g (73%) of6,11-dihydro-11-oxodibenz[b,e]oxepin-3-carboxaldehyde oxime, mp170°-172° C.

C,H,N analysis Calcd for C₁₅ H₁₁ NO₃ : C, 71.14; H, 4.37; N, 5.53.Found: C, 71.10; H, 4.06; N, 5.41.

EXAMPLE 16 3[(Hydroxyamino)methyl]dibenz[b,e]oxepin-11(6H)-one

Sodium cyanoborohydride (13.6 g, 0.22 mol) is added in portions to asolution of 6,11-dihydro-11-oxodibenz[b,e]oxepin-3-carboxaldehyde, oxime(11 g; 0.04 mol) in acetic acid (150 ml) at 15°-20° C. (cooling). Afterthe mixture is stirred for 2.5 hours, an additional portion of sodiumcyanoborohydride (2 g) is added and the solution is stirred for anadditional 2 and 3/4 hours. The mixture is neutralized to pH ˜7 with 50%sodium hydroxide solution, the temperature being maintained at 65° C.The product is extracted with ethyl acetate, followed by washings withwater, saturated sodium chloride solution, drying and evaporating underreduced pressure to give 13.2 g of a solid residue. The residue is flashchromatographed on silica gel with chloroform then withchloroform:methanol=95:5, as eluant to give 8.66 g (78%);3[(hydroxyamino)methyl]dibenz[b,el]oxepin-11(6H)-one, as a solid.

EXAMPLE 17 N[(6,11-Dihydro-11-oxodibenz[b,el]oxepin-3-yl)methyl]N-hydroxy-2-methylpropanamide

To a solution of 3[(hydroxyamino) methyl]dibenz[b,e]oxepin-11(6H)-one(5.5 g, 0.02 mol) sodium acetate (5.8 g, 0.04 mol) in dioxane (120 ml)and water (60 ml) isobuturyl chloride (2.55 g, 0.023 mol) is added.After the mixture is stirred for one hour at room temperature, lithiumhydroxide (1 g) is added and the solution is stirred for 18 hours. Themixture is acidified with 1N hydrochloric acid, poured into ice waterand extracted with ethyl acetate. The organic layer is washedsuccessively with water, sodium bicarbonate solution and water, driedover sodium sulfate and evaporated to give 7.1 g of oily residue. Flashchromatography on silica gel with methylene chloride:methanol=95:5 aseluant, gives 5.3 g of the product. Further purification is accomplishedby flash chromatography on silica gel with methylene chloride:ethylacetate=80:20 as eluant giving 3.4 g of a solid, which onrecrystallization from methylene chloride-hexane, yielded 2.6 g (37%) ofanalytically pureN-[6,11-dihydro-11-oxodibenz[b,el]oxepin-3-yl]methyl]-N-hydroxy-2-methylpropanamide,mp 128°-131° C.

C,H,N analysis Calcd for C₁₉ H₁₉ NO₄ : C, 70.16; H, 5.89; N, 4.31.Found: C, 70.25; H, 5.88; N, 4.21.

EXAMPLE 18N-[(6,11-Dihydro-11-oxodibenz[b,el]oxepin-3-yl)methyl]-N-hydroxyacetamide

Sodium cyanoborohydride (3 g, 0.047 mol) is added in portions to asuspension of 6,11-dihydro-11-oxodibenz[b,el]oxepin-3-carboxaldehyde,oxime (4 g, 0.016 mol) in acetic acid (70 ml) at ca 15° C. (cooling).After the mixture is stirred for four hours at room temperature, aceticanhydride (1.8 g) is added. The solution is stirred at room temperaturefor 3 and 1/4 hours, poured into ice water and extracted with ethylacetate. The organic layer is separated and washed successively with 1Nhydrochloric acid, water, sodium bicarbonate solution and water, thendried and evaporated to give 3.9 g of a residue. The residue was treatedwith lithium hydroxide (1.8 g), methanol (30 ml), water (10 ml), thenstirred for one hour. The mixture is then poured into water, acidifiedand the product is isolated with ethyl acetate to give 3.2 g of oilyresidue. Flash chromatography on silica gel with methylenechloride:ethyl acetate=8:2, then with ethyl acetate as eluant yields 2.6g of a residue. Repeat flash rechromatography on silica gel withchloroform:methanol=9:1 as eluant gives 2.2 g (47%)N-[(6,11-dihydro-11-oxodibenz[b,e]oxepin-3-yl]methyl]-N-hydroxyacetamide,as a solid, mp 65°-115° C.

C,H,N analysis Calcd for C₁₇ H₁₅ NO₄ : C, 68.67; H, 5.08; N, 4.71.Found: C, 68.14; H, 5.14, N, 4.48.

EXAMPLE 19Ethyl[[(6,11-Dihydro-11-oxodibenz[b,e]oxepin-3-yl)methyl]hydroxyamino]oxoacetate

To a solution of 3[(hydroxyamino) methyl]dibenz[b,e]oxepin-11(6H)-one(4.25 g, 0.016 mol), sodium acetate (4.5 g, 0.03 mol) in dioxane (90 ml)and water (40 ml) at 520°-10° C. is added ethyl oxalylchloride (2.27 g,0.016 mol). The mixture is stirred at 5°-10° C. for 30 minutes, then atroom temperature for three hours, poured into ice water and extractedwith ethyl acetate. The ethyl acetate layer is washed successively withwater, sodium bicarbonate solution and water, then dried and evaporatedto give 5.2 g of oily residue. Flash chromatography on silica gel, thenrechromatography with methylene chloride:methanol=95:5, as eluant gives1.6 g (27%) of ethyl[[(6,11-dihydro-11-oxodibenz[b,e]oxepin-3-yl)methyl]hydroxyamino]oxoacetate,as a solid, mp 52°-62° C.

C,H,N analysis Calcd for C₁₉ H₁₇ NO₆ : C, 64.22; H, 4.82; N, 3.90.Found: C, 63.91; H, 4.79; N 3.66.

EXAMPLE 20 N-[(6,11-Dihydro-11-oxodibenz[b,e]oxepin-3-yl)methyl]-N-hydroxy-N'-methylurea

Methylisocyanate (0.89 g, 0.016 mol) in toluene (10 ml) is addeddropwise to a solution of3[(hydroxyamino)methyl]dibenz[b,el]oxepin-11(6H)-one (4 g, 0.016 mol) intoluene (50 ml) and tetrahydrofuran (50 ml). The mixture is stirred for18 hours at room temperature to give 2.48 g (51%) of the desiredproduct, mp 155°-157°]C. Recrystallization from methanol-ethylacetategives 1.75 g (36%) ofN[(6,11-dihydro-11-oxodibenz[b,el]oxepin-3-yl)methyl]-N-hydroxy-N'-methylurea,as a white crystalline solid, mp 156°-158° C.

C,H,N analysis Calcd for C₁₇ H₁₆ N₂ O₄ ; C, 65.37; H, 5.16; N, 8.97.Found: C, 65.29; H, 5.17; N, 8.93.

EXAMPLE 21 4-(1,3-Dihydro-1-oxo-2H-isoindol-2-yl)benzoic acid, ethylester

A mixture of o-phthalicdicarboxaldehyde (17.54 g, 0.131 mol) andp-carbethoxyphenylisocyanate (25.0 g, 0.131 mol) is heated in an oilbath at 170° C. for 4.0 hours under nitrogen atmosphere. The hot melt isthen slowly poured into CHCl₃ (300 ml). The solution is then evaporatedto dryness when a solid residue is obtained. The crude4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)benzoic acid, ethyl ester istriturated with isopropyl ether and then recrystallized from CH₂ Cl₂--isopropyl ether (1:1, 300 ml) to give white solid. Yield 5.07 g(13.8%); mp 182°-184° C.

Anal. Calcd for C₁₇ H₁₅ NO₃ : C, 72.58; H, 5.37; N, 4.98. Found: C,72.52; H, 5.41; N, 4.81.

EXAMPLE 22 4-(1,3-Dihydro-1-oxo-2H-isoindol-2-yl)benzoic acid

A mixture of 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)benzoic acid, ethylester (2.55 g, 0.009 mol), 1N NaOH (20 ml), water (70 ml), and methanol(70 ml) is heated to reflux for 20 minutes when a clear solution isformed. The reaction mixture is filtered and the filtrate is carefullyacidified with 4N HCl (6 ml) to pH 1.0 when a solid pptd. out. The crude4-(1,3-Dihydro-1-oxo-2H-isoindol-2-yl)benzoic acid is filtered, washedwith hot CH₃ OH and dried to give analytical sample. Yield 1.67 g (73%);mp >295° C.

Anal. Calcd for C₁₅ H₁₁ NO₃ : C, 71.14; H, 4.37; N, 5.53. Found: C,71.03; H, 4.37; N, 5.47.

Examples 21 and 22 are useful as representative preparations ofintermediates for the preparation of aldehydes shown as I in Scheme A.

EXAMPLE 23 2-(4-Acetylphenyl)-2,3-dihydro-1H-isoindole-1-one

A mixture of 4-acetylphenylisocyanate (27.5 g, 0.17 mol) ando-phthalicdicarboxaldehyde (25.0 g, 0.186 mol) is heated in an oil bathat 170°-175° C. for 4.0 hours under nitrogen atmosphere. On cooling themelt solidified which is pulverized and refluxed with CH₂ Cl₂ and CH₃ OHand filtered to give 18.2 g (41.4%) of the desired2-(4-acetylphenyl)-2,3-dihydro-1H-isoindole-1-one, mp 235°-237° C. Theresidue is recrystallized from DMF (1800 ml). Yield 13.0 g (29.6%), mp236-239° C. (Jap. patent J5 7050-960; mp 243°-244° C. for thenonsolvated compound, prepared by a different route).

Anal. Calcd for C₁₆ H₁₃ NO₂.0.10DMF: C, 75.70; H, 5.34; N, 5.96. Found:C, 75.35; H, 5.15; N, 5.51.

EXAMPLE 242,3-Dihydro-2-(4-(1-hydroxyimino)ethyl)phenyl)-1H-isoindole-1-one

A mixture of 2-(4-acetylphenyl)-2,3-dihydro-1H-isoindole-1-one (2.6 g,0.01 mol), hydroxylamine.HCl (2.1 g, 0.03 mol) and pyridine (25 ml) isheated at 100° C. for 4.0 hours when a clear solution is formed. It isallowed to cool to 24° C. when2,3-dihydro-2-(4(1-hydroxyimino)ethyl)phenyl)-1H-isoindole-1-onecrystallized out. Yield 2.65 g (100%); mp 265°-269° C. (dec).

Anal. Calcd for C₁₆ H₁₄ N₂ O₂ : C, 72.16; H,5.30; N, 10.52 Found: C,71.36, 71.93; H, 5.28, 5.51; N, 10.34, 10.64.

EXAMPLE 25 2-[(2,6-Dichlorophenyl)amino]benzoic acid, methyl ester

To a solution of 2-[(2,6-dichlorophenyl) amino]benzoic acid (25 g, 89mmol) [J. S. Kaltenbronn et al, Arzneim-Forsch/Drug Res. 33(1),4a,621-627 (1983)] and dimethylformamide (6.8 g, 93 mmol) in drytetrahydrofuran (500 ml) is added oxalyl chloride (17 ml, 196 mmol)dropwise with stirring under an atmosphere of dry nitrogen at 0° C. Theice bath is removed and the reaction mixture is stirred without coolingfor 15 minutes. The reaction mixture is poured into methanol (1500 ml).The solvent is evaporated and the residue is partitioned between ethylacetate and saturated aqueous sodium bicarbonate. The organic layer isdried (MgSO₄) and evaporated. Recrystallization of the residue frommethanol provides pure 2-[(2,6-dichlorophenyl) amino]benzoic acid,methyl ester (21.9 g, 83%); mp 100°-103° C.

Anal. Calcd for C₁₄ H₁₁ Cl₂ NO₂ : C, 56.78; H, 3.74; N, 4.73. Found: C,56.71; H, 3.73; N, 4.79.

Cl Calcd 23.94. Found: 23.17.

EXAMPLE 26 2-[(2,3-Dimethylphenyl)amino]benzoic acid, methyl ester

A suspension of 2-[(2,3-dimethylphenyl) amino]benzoic acid (mefenamicacid) 35 g, 145 mmol) in methanol (600 ml) and concentrated sulfuricacid (15 ml) is heated at reflux for two days. The reaction mixture iscooled in an ice bath. The resulting solid is collected by filtrationand recrystallized from methanol to give2-[(2,3dimethylphenyl)amino]benzoic acid, methyl ester (32.0 g, 86%); mp98°-100° C.

Anal. Calcd for C₁₆ H₁₇ NO₂ : C, 75.27; H, 6.71; N, 5.49. Found: C,75.29; H, 6.75; N, 5.46.

EXAMPLE 27 2-[(2,6-Dichloro-3-methylphenyl)amino]benzoic acid, methylester

2-[(2,6-Dichloro-3-methylphenyl)amino]benzoic acid is reacted withoxalyl chloride and methanol according to the procedure of Example 25 togive 2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid, methyl ester in89% yield; mp 132°-134° C.

EXAMPLE 28 2-[[3-(Trifluoromethyl)phenyl]amino]benzoic acid, methylester

Reaction of 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid withmethanol and sulfuric acid according to the procedure of Example 26gives a 71% yield of 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid,methyl ester as a colorless oil.

EXAMPLE 29 2-[(2,3-Dimethylphenyl)amino]benzyl alcohol

A solution of 2-[(2,3-dimethylphenyl) amino]benzoic acid, methyl ester(31 g, 121.5 mmol) in dry ether (600 ml) is added dropwise to asuspension of lithium aluminum hydride (6.9 g, 0.18 mmol) in dry ether(200 ml) under an atmosphere of dry nitrogen. The reaction mixture isstirred at room temperature overnight and quenched by the carefuldropwise addition of water (7 ml), 15% NaOH (7 ml) and water (20 ml).The resulting suspension is filtered and the filtrate is evaporated toan oil which crystallizes upon addition of hexane to give pure2-[(2,3-dimethylphenyl)amino]benzyl alcohol (26 g, 94%); mp 65°-69° C.

Anal. Calcd for C₁₅ H₁₇ NO: C, 79.26; H, 7.54; N, 6.16. Found: C, 79.20;H, 7.54; N, 6.05.

The following compounds are prepared according to the procedure ofExample 29:

    ______________________________________                                         ##STR23##                                                                                                         Prepared                                                                      from the                                                                      Compound                                 Example               mp       %     of the                                   No.    Q              °C.                                                                             Yield Example                                  ______________________________________                                        30                                                                                    ##STR24##     109-112  97%   Ex. 25                                   31                                                                                    ##STR25##     145-146  75%   Ex. 27                                   32                                                                                    ##STR26##     oil      89%   Ex. 28                                   ______________________________________                                    

EXAMPLE 33 2-[(2,3-Dimethylphenyl)amino]-benzaldehyde

A suspension of pyridinium chlorochromate (47.5 g, 0.22 mol) and neutralalumina (170 g) in dichloromethane (600 ml) is stirred for 30 minutes atroom temperature. 2-[(2,3-dimethylphenyl)amino]benzyl alcohol (25 g,0.11 mol) is added and the reaction mixture is stirred at roomtemperature overnight. The suspension is filtered through a pad ofsilica gel (1000 g) and the product is eluted with dichloromethane (2500ml). The combined filtrate and eluant are evaporated and the residue isrecrystallized from cold methanol/water to give2-[(2,3-dimethylphenyl)amino]benzaldehyde (11.95 g, 48%).Recrystallization from hexane at 0° C. gives analytical material; mp45°-47° C.

Anal. Calcd for C₁₅ H₁₅ NO C, 79.97; H, 6.71; N, 6.22. Found: C, 79.84;H, 6.75; N, 6.38.

The following compounds are prepared according to the procedure ofExample 33:

    ______________________________________                                         ##STR27##                                                                                                         Prepared                                                                      from the                                                                      Compound                                 Example               mp       %     of the                                   No.    Q              °C.                                                                             Yield Example                                  ______________________________________                                        34                                                                                    ##STR28##     108-112  76%   Ex. 30                                   ______________________________________                                    

Anal. Calcd for C₁₃ H₉ Cl₂ NO: C, 58.67; H, 3.41; N, 5.26; Cl, 26.64.Found: C, 58.73; H, 3.38; N, 5.10; Cl, 26.78.

    ______________________________________                                                                             Prepared                                                                      from the                                                                      Compound                                 Example               mp       %     of the                                   No.    Q              °C.                                                                             Yield Example                                  ______________________________________                                        35                                                                                    ##STR29##     90-91    73%   Ex. 31                                   Anal. Calcd. for C.sub.14 H.sub.11 Cl.sub.2 NO:                               C, 60.02; H, 3.97; N, 5.00; Cl, 25.31.                                        Found: C, 60.15; H, 3.96; N, 4.98; Cl, 25.42.                                 36                                                                                    ##STR30##     54-56    64%   Ex. 32                                   Anal. Calcd. for C.sub.14 H.sub.10 F.sub.3 NO:                                C, 63.39; H, 3.81; N, 5.28; Cl, 21.49.                                        Found: C, 63.56; H, 3.81; N, 5.23; Cl, 21.03.                                 ______________________________________                                    

A solution of 2-[(2,3-dimethylphenyl)amino]benzaldehyde (11 g, 0.049mol) and hydroxylamine hydrochloride (17 g, 0.25 mol) in pyridine (250ml) is stirred at room temperature overnight. The solvent is evaporatedand the residue is partitioned between ethyl acetate (200 ml) and 10%aqueous HCl (200 ml). The organic layer is washed with 10% aqueous HCl(200 ml) and water (2×100 ml). The organic layer is dried (MgSO₄) andthe solvent is evaporated to give 2-[(2,3-dimethylphenyl)amino]benzaldehyde oxime which is recrystallized from hexane. Yield 7.3g (62%); mp 107°-108° C.

Anal. Calcd for C₁₅ H₁₆ N₂ O: C, 74.97; H, 6.71; N, 11.66 Found: C,75.32; H, 6.69; N, 11.34

The following compounds are prepared according to the procedure ofExample 37:

    ______________________________________                                         ##STR31##                                                                                                         Prepared                                                                      from the                                                                      Compound                                 Example               mp       %     of the                                   No.    Q              °C.                                                                             Yield Example                                  ______________________________________                                        38                                                                                    ##STR32##     82-85    78%   Ex. 34                                   Anal. Calcd for C.sub.13 H.sub.10 Cl.sub.2 N.sub.2 O:                         C, 55.54; H, 3.59; N, 9.96; Cl, 25.22                                         Found: C, 55.38; H, 3.53; N, 9.92; Cl, 25.36                                  39                                                                                    ##STR33##     oil      78%   Ex. 35                                   Anal. Calcd. for C.sub.14 H.sub.12 Cl.sub.2 N.sub.2 O.0.13H.sub.2 O:          C, 56.51; H, 4.16; N, 9.42; Cl, 23.83;                                        H.sub.2 O, 0.79                                                               Found: C, 56.16; H, 4.44; N, 9.09; Cl, 23.08;                                  H.sub.2 O, 0.44                                                              40                                                                                    ##STR34##     oil      91%   Ex. 36                                   ______________________________________                                    

EXAMPLE 41 2-[(2,3-Dimethylphenyl)amino]-N-hydroxybenzenemethanamine

To a solution of 2-[(2,3-dimethylphenyl)amino]benzaldehyde oxime (2.0 g,8.4 mmol) and methyl orange (20 mg as an indicator), in methanol (40 ml)and water (10 ml) is added sodium cyanoborohydride (4.0 g, 64 mmol) insmall portions over two hours, maintaining a red color of the indicatorby the dropwise addition of concentrated HCl. The reaction of mixture isdiluted with ethyl acetate (200 ml) and the aqueous layer is neutralizedto pH=7 with 1N NaOH. The organic layer is collected, dried (MgSO₄) andthe solvent is evaporated to give crude2-[(2,3-dimethylphenyl)amino]-N-hydroxy-benzenemethanamine as an oilwhich is used without further purification in the next step.

EXAMPLE 42 2-[(2,6-Dichlorophenyl)amino]-N-hydroxybenzenemethanamine

To a solution of 2-[(2,6-dichlorophenyl)amino]benzaldehyde oxime (4.0 g,13.6 mmol) in glacial acetic acid (20 ml) is added sodiumcyanoborohydride (2.05 g, 33 mmol) in small portions over a period oftwo hours. The reaction mixture is diluted with ethyl acetate (200 ml)and neutralized with 1N NaOH. The organic layer is collected and thesolvent is evaporated.2[(2,6-Dichlorophenyl)amino]-N-hydroxybenzenemethanamine (3.5 g, 91%) isisolated as an oil by flash chromatography (silica, 3:1 chloroform/ethylacetate). The compound is not further purified, but used directly in thenext reaction.

The following compounds are prepared according to the procedure ofExample 41 and 42.

    __________________________________________________________________________     ##STR35##                                                                                              Prepared from                                                                         Prepared by                                                    mp %   Compound of                                                                           Method of                                   Example No.                                                                          Q        R  °C.                                                                       Yield                                                                             Example Example                                     __________________________________________________________________________    42                                                                                    ##STR36##                                                                             H  oil                                                                              91% 38      42                                          43                                                                                    ##STR37##                                                                             H  oil                                                                              43% 39      41                                          44                                                                                    ##STR38##                                                                             H  oil                                                                              70% 40      42                                          45                                                                                    ##STR39##                                                                             Me oil                                                                              45% 52      41                                          __________________________________________________________________________

EXAMPLE 47N-[[2-[(2,3-Dimethylphenyl)amino]phenyl]methyl-N-hydroxyacetamide

Acetyl chloride (0.53 g, 6.8 mmol) is added dropwise at 0° C. to asolution of 2-[(2,3-dimethylphenyl)amino]-N-hydroxybenzenemethanamine(1.64 g, 6.8 mmol) and sodium acetate (840 mg, 0 mmol) in 2:1dioxane/water (100 ml). The reaction mixture is stirred at roomtemperature for 30 minutes. The product is extracted into ethyl acetate.The organic layer is washed with brine, dried over magnesium sulfate andevaporated to a residue which is recrystallized from cyclohexane to givepure N-[[2-[(2,3-dimethylphenyl)amino]phenyl]methyl]-N-hydroxyacetamide(1.02 g, 53%); mp 93°-98° C.

Anal. Calcd for C₁₇ H₂₀ N₂ O₂ : C, 71.81; H, 7.09; N, 9.85. Found: C,71.51; H, 6.93; N, 9.65.

EXAMPLE 48N-[[(2,6-Dichlorophenyl)amino]phenyl]methyl-N-hydroxyacetamide

A solution of 2-[(2,6-dichlorophenyl)amino]-N-hydroxybenzenemethanamine(2.0 g, 7 mmol) and triethylamine (2.12 g, 21 mmol) in dichloromethane(100 ml) is treated with acetyl chloride (1.1 ml, 15.5 mmol) dropwisewith stirring, under an argon atmosphere. The reaction mixture isstirred for 50 minutes at room temperature and then washed with water(3×200 ml). The solvent is evaporated and the residue recrystallizedfrom hexane to give the crude intermediate bis-acetyl derivative whichis dissolved with warming in isopropanol (200 ml). The solution istreated with a solution of lithium hydroxide (0.84 g, 35 mmol) in water(30 ml). The reaction mixture is stirred at room temperature for 30minutes and is neutralized by the addition of 1N HCl. The reactionmixture is diluted with water (300 ml) and the product is extracted intoethyl acetate. The solvent is removed and the residue is recrystallizedfrom isopropyl ether/ethyl acetate to give pureN-[[(2,6-dichlorophenyl)amino]phenyl]methyl-N-hydroxyacetamide (600 mg,26%); mp 165°-171° C.

Anal. Calcd for C₁₅ H₁₄ Cl₂ N₂ O₂ : C, 55.40; H, 4.34; N, 8.61; Cl,21.80. Found: C, 55.20; H, 4.14; N, 8.43; Cl, 21.66.

EXAMPLE 491-[2-[(2,6-Dichloro-3-methylphenyl)amino]phenyl]-2-(methylsulfinyl)ethanone

2-[(2,6-Dichloro-3-methylphenyl)amino]benzoic acid methyl ester (3.3 g,10.6 mmol) is dissolved in 30 ml of dry THF and added to a solution ofdimsyl anion (JACS, 84, 866, 1982) (31.9 mmol) in 60 ml of 1:1 DMSO/THFat 0° C. under argon. When addition is complete, the ice bath is removedand the reaction mixture is stirred at room temperature for five hours.The reaction is quenched with 400 ml of 1N hydrochloric acid, andextracted twice with 300 ml of chloroform. The combined chloroformextract is washed with 300 ml of water three times, and once with 300 mlof brine. This chloroform layer is dried over magnesium sulfate andevaporated. The residue solidifies after being dried at room temperatureunder vacuum for 12 hours. Recrystallization from methylene chloride inhexane gives 1.0 g of1-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]-2-(methylsulfinyl)ethanone(26% yield); mp 152°-154 ° C.

Anal. Calcd for C₁₆ H₁₅ Cl₂ NO₂ S: C, 53.94; H, 4.25, N, 3.93, Cl,19.90, S, 9.00. Found: C, 54.00; H, 4.26; N, 3.91; Cl, 19.74; S, 8.93.

EXAMPLE 50 1-[2-[(2,6-Dichloro-3-methylphenyl)amino]phenyl]ethanone

1-[2-[(2,6-Dichloro-3-methylphenyl)amino]phenyl]-2-(methylsulfinyl)ethanone(2.0 g, 5.61 mmol) is dissolved in 100 ml of 10% water/tetrahydrofuranand cooled to 0° C in an ice bath. Aluminum amalgam is prepared byaddition of aluminum foil (1.5 g, 56.1 mmol) to 350 ml of 2% aqueousmercuric chloride. After 15 seconds, the liquid is decanted, and thefoil is washed twice with absolute ethanol followed by tetrahydrofuran.The freshly prepared aluminum amalgam is added to the reaction mixturewhich is then stirred for 30 minutes at 0° C. The reaction mixture isfiltered through celite, and the solids are washed with tetrahydrofuran.The filtrate is evaporated, and the residue is taken up in ether. Theether solution is washed with 100 ml of water and dried over magnesiumsulfate. Evaporation of the solvent gives a yellow solid which isrecrystallized from diethyl ether/hexane. Yield (1.0 g, 60%) of1-[2-[(2,6-dichloro-3 -methylphenyl)amino]phenyl]ethanone; mp 122°-125°C.

Anal. Calcd for C₁₅ H₁₃ Cl₂ NO: C, 61.24; H, 4.46; N, 4.76. Found: C,61.26; H, 4.51; N, 4.71.

EXAMPLE 51 1-[2-[(2,6-Dichloro-3-methylphenyl)amino]phenyl]ethanone

2-[(2,6-Dichloro-3-methylphenyl)amino]benzoic acid (8.4 g, 28.5 mmol)and carbonyl diimidazole (6.9 g, 42.7 mmol) are stirred in 300 ml THFunder argon for two hours. Malonic acid monoethyl ester, magnesium salt(24.0 g, 85.4 mmol) is added and the reaction mixture is warmed toreflux for 15 hours. The solvent is evaporated, and the residuepartitioned between ethyl acetate and 1N HCl. The pH of the aqueouslayer is adjusted to pH=1 with concentrated HCl. The aqueous layer isextracted with ethyl acetate. The organic layer is washed with 1N HCl,and with saturated sodium bicarbonate, and then dried over magnesiumsulfate and evaporated. The solid remaining is taken up in ethyl acetateand adsorbed onto a silica gel pad. The pad is washed with chloroform.Evaporation of the chloroform gives crude β-keto ester which is treatedwith 30% water/trifluoroacetic acid at reflux for two hours. Thetrifluoroacetic acid is evaporated, and the residue is taken up indiethyl ether. The ether solution is washed with 100 ml of saturatedsodium bicarbonate three times. It is dried over magnesium sulfate, andevaporated. The remaining solid is taken up in methylene chloride andadsorbed onto a silica gel pad. This pad is washed with methylenechloride. Evaporation of the solvent gives a yellow solid.Recrystallization from methylene chloride/hexane gives 6.5 g (42%) of1-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]ethanone; mp 130° -132°C.

Anal. Calcd for C₁₅ H₁₃ Cl₂ NO: C 61.24; H, 4.46; N, 4.76. Found: C,61.09; H, 4.45; N, 4.74.

EXAMPLE 52 1-[2-[(2,6-Dichloro-3-methylphenyl)amino]phenyl]ethanoneoxime

1-[2-[(2,6-Dichloro-3-methylphenyl)amino]phenyl]ethanone (0.8 g, 2.7mmol) and hydroxylamine hydrochloride (0.8 g, 10.8 mmol) are dissolvedin 15 ml of pyridine under argon at room temperature for 12 hours. Thepyridine is evaporated, and the residue partitioned between methylenechloride and water. The organic layer is washed twice with 100 ml ofwater and dried over magnesium sulfate. The solution is concentrated onthe rotovap and passed through a silica gel pad which is then elutedwith methylene chloride. The solvent is evaporated and1-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]ethanone oxime isrecrystallized from H₂ O/MeOH. Yield 0.2 g (24%); mp 116°-118° C.

Anal. Calcd for C₁₅ H₁₄ Cl₂ N₂ O: C, 58.26; H, 4.57; N, 9.06; Cl, 22.93.Found: C, 58.32; H, 4.60; N, 8.82; Cl, 22.93.

EXAMPLE 53N-[1-[2-[(2,6-Dichloro-3-methylphenyl)amino]phenyl]ethyl]-N-hydroxyacetamid

2-[(2,6-Dichloro-3-methylphenyl)amino]-N-hydroxy-α-methylbenzenemethanamine(1.2 g, 3.8 mmol) is reacted with acetyl chloride (0.66 g, 8.5 mmol),triethylamine (1.2 g, 11.6 mmol), and lithium hydroxide (0.46 g, 19.3mmol) according to the procedure of Example 48 to giveN-[1-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]ethyl]-N-hydroxyacetamide(0.6 g, 45% yield); mp 185°-187° C.

Anal. Calcd for C₁₇ H₁₈ Cl₂ N₂ O₂ : C, 57.79; H, 5.15; N, 7.93; Cl,20.07. Found: C, 57.91; H, 5.00; N, 7.64; Cl, 20.13.

EXAMPLE 54N-[[2-[(2,6-Dichloro-3-methylphenyl)amino]phenyl]methyl]-N-hydroxyacetamide

2-[(2,6-Dichloro-3-methylphenyl)amino]-N-hydroxybenzenemethanamine (1.00g, 3.4 mmol) is reacted with acetyl chloride (0.58 g, 7.4 mmol),triethylamine (1.0 g, 10.1 mmol), and lithium hydroxide (0.40 g, 16.8mmol) according to the procedure of Example 48 to give 0.5 g (43% yield)ofN-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methyl]-N-hydroxyacetamide;mp 155°-156° C.

Anal Calcd for C₁₆ H₁₆ Cl₂ N₂ O₂ : C, 56.64; H, 4.76; N, 8.26; Cl,20.90. Found: C, 56.68; H, 4.61; N, 8.10; Cl, 21.39.

EXAMPLE 55N-Hydroxy-N-[[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]methylacetamide

2-[[3-(Trifluoromethyl)phenyl]amino]-N-hydroxybenzenemethanamine (2.0 g,7.1 mmol) is reacted with sodium acetate (0.87 g, 10.6 mmol) and acetylchloride (0.56 g, 7.1 mmol) according to the procedure of Example 47 togive 1.2 g (52% yield) ofN-hydroxy-N-[[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]methylacetamide;mp 124°-125° C.

Anal. Calcd for C₁₆ H₁₅ F₃ N₂ O₂ : C, 59.25; H, 4.67; N, 8.64; F, 17.57.Found: C, 58.85; H, 4.73; N, 8.49; F, 17.69.

EXAMPLE 56 N-Hydroxy-N'-methyl-N-[[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]methylurea

2-[[3-(Trifluoromethyl)phenyl]amino]-N-hydroxybenzenemethanamine (3.1 g,11.0 mmol) is dissolved in 75 ml of 2:1 dioxane/water and cooled to -10°C. in an ice-salt water bath. Methyl isocyanate (1 eq) is added dropwiseat -10° C., and the reaction mixture is kept at that temperature for 10minutes. The reaction mixture is quenched with water and extracted withethyl acetate. The ethyl acetate extract is washed with brine, and driedover magnesium sulfate. The solvent is evaporated, andN-hydroxy-N'-methyl-N-[[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]methylurea is recrystallized from methylene chloridein hexane. Yield 1.1 g, 29%; mp 138°-139° C.

Anal. Calcd for C₁₆ H₁₆ F₃ N₃ O₂ C, 56.63; H, 4.76; N, 12.39; F, 16.80.Found: C, 56.61; H, 4.77; N, 12.27; F, 16.78.

EXAMPLE 57N-Hydroxy-N-[[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]methyl]carbamicacid, ethyl ester

2-[[3-(Trifluoromethyl)phenyl]amino]-N-hydroxybenzenemethanamine isreacted with ethyl chloroformate according to the procedure of Example47 to obtainN-hydroxy-N-[2-[[3-(trifluoromethyl)phenyl]amino]methyl]carbamic acid,ethyl ester; mp 82°-84° C.

EXAMPLE 58 5-Methoxy-2-methyl-1H-indole-3-carboxaldehyde

Phosphorous oxychloride (12.7 ml, 0.136 mol) is added dropwise at 0° C.to dimethylformamide (42.4 ml, 0.544 mol) over 30 minutes. A solution of5-methoxy-2-methylindole (20 g, 0.124 mol) in 40 ml of DMF is addeddropwise over 45 minutes. When 30 ml of the indole solution has beenadded, it becomes necessary to add 10 ml of DMF to break up the heavypaste which forms. The reaction mixture is then warmed to 35° C. for onehour. After 30 minutes the reaction again becomes too pasty, and 5 mlmore of DMF is added. The bath is removed, and 60 g of crushed ice isadded quickly to the reaction mixture. The reaction mixture is stirredfor 30 minutes followed by addition of 20 ml of water and 40 g of ice. Asolution of sodium hydroxide (25 g) in water (200 ml) is added dropwiseto the red solution. After the first one-third of this sodium hydroxidesolution has been added, the color changes to yellow, and the remainderof the sodium hydroxide solution is added quickly. It is rapidly broughtto a boil (100°-120° C.) for 10 minutes, cooled and refrigeratedovernight. The solid is filtered and washed four times with cool water.It is dried in a vacuum oven at 50° C. for 22 hours to give 23.0 g (98%)of powdery yellow crystals of pure5-methoxy-2-methyl-1H-indole-3-carboxaldehyde; mp 190°-191° C.

Anal. Calcd for C₁₁ H₁₁ NO₂ : C, 69.83; H, 5.86; N, 7.40. Found: C,69.48; H, 5.87; N, 7.41.

EXAMPLE 591-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-carboxaldehyde

To a solution of 5-methoxy-2-methyl-1H-indole-3carboxaldehyde (20 g, 106mmol) in 210 ml of dry dimethylformamide is added oil free sodiumhydride (2.7 g, 111 mmol). The reaction mixture is stirred for fivehours at which time it is cooled to -60° C., and freshly distilled4-chlorobenzoyl chloride (14.4 ml, 117 mmol) is added dropwise. It isstirred for an additional 10 minutes and worked up by pouring the coldpaste into cold ethyl acetate and water. The organic phase is washedonce with dilute sodium bicarbonate solution, once again with water, andonce with a saturated solution of sodium chloride. It is further driedwith magnesium sulfate, filtered, and concentrated in vacuo to a solidwhich is stirred vigorously with 50 ml of methanol for two hours. Thesolid is filtered and dried to give1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-carboxaldehyde (28.7g, 82.5%). A portion which is recrystallized from ethyl acetate has a mpof 150.5°-151.5° C.

Anal. Calcd for C₁₈ H₁₄ ClNO₃ : C, 65.96; H, 4.31; N, 4.27; Cl, 10.82.Found: C, 65.87; H, 4.28; N, 4.16; Cl, 10.54.

EXAMPLE 601-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-carboxaldehyde, oxime

To a solution of1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-carboxaldehyde (5.9g, 18 mmol) in 90 ml of freshly distilled tetrahydrofuran at 0° C. isadded anhydrous sodium acetate (4.4 g, 54 mmol) and anhydroushydroxylamine hydrochloride (2.0 g, 28.8 mmol). After five minutes theice bath is removed, and the reaction mixture is stirred for threehours. The reaction mixture is diluted with ethyl acetate and water. ThepH of the aqueous layer is adjusted to pH=3-4 with dilute HCl. Theorganic layer is washed once with 10% sodium bicarbonate, once withwater, and finally with a saturated solution of sodium chloride. It isfurther dried over magnesium sulfate, filtered, and concentrated invacuo. The residue is purified by column chromatography (silica gel, 1:9ethyl acetate:methylene chloride) to give 4.17 g (68%) of1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-carboxaldehyde,oxime. A sample which is recrystallized fromtetrahydrofuran:methanol:water softens at 180° C. and melts at 196°-197°C.

Anal. Calcd for C₁₈ H₁₅ ClN₂ O₃ : C, 63.07; H, 4.41; N, 8.17. Found: C,62.85; H, 4.34; N, 8.01.

EXAMPLE 611-(4-Chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine

To a suspension of1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-carboxaldehyde, oxime(1.0 g, 2.9 mmol) in 15 ml of acetic acid is added 0.9 g (14.6 mmol) ofsodium cyanoborohydride (0.9 g, 14.6 mmol). The reaction mixture isstirred vigorously for three hours whereupon an additional 0.35 g (5.6mmol) of the reducing agent is added. After an additional 45 minutes thereaction mixture is diluted with ethyl acetate and methylene chloride,cooled to 0° C., and 300 ml of a saturated solution of sodiumbicarbonate is added dropwise while continuing to stir vigorously. Thismixture is diluted further with 400 ml of ethyl acetate and separatedfrom the aqueous phase (pH=9). The organic phase is washed again with asaturated solution of sodium bicarbonate, water, and finally a saturatedsolution of sodium chloride. It is dried over magnesium sulfate,filtered, and concentrated to a yellow oil which is crude1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamineand is used without further purification in the subsequent reaction.Mass balance is quantitative. A sample recrystallized from methylenechloride has a mp of 164°-165° C. (dec).

Anal. Calcd for C₁₈ H₁₇ ClN₂ O₃ : C, 62.70; H, 4.97; N, 8.12; Cl, 10.28.Found: C, 62.01; H, 4.90; N, 7.96; Cl, 10.99.

EXAMPLE 62N-[[1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl]methyl]-N-hydroxyacetamide

To a suspension of1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine(1,2 g, 3.5 mmol) and sodium acetate (730 mg, 8.9 mmol) in 120 ml of1,4-dioxane and 30 ml of water is added dropwise acetyl chloride (420μl, 5.9 mmol) at 0° C. After 10 minutes additional acetyl chloride (40μl, 0.6 mmol) is added. The reaction mixture is stirred for 15 minutes,and then is diluted with ethyl acetate. It is washed once with a dilutesolution of sodium bicarbonate, once with water, and a saturatedsolution of sodium chloride. The organic phase is further dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residue ispurified by column chromatography on silica gel, eluting first with 1:4ethyl acetate:methylene chloride then 1:1 ethyl acetate:methylenechloride. Recrystallization from isopropyl ether givesN-[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]-N-hydroxy-acetamide(645 mg, 47%); mp 160°-161° C.

Anal. Calcd for C₁₈ H₁₇ ClN₂ O₃ : C, 62.10; H, 4.95; N, 7.24; Cl, 9.16.Found: C, 61.98; H, 4.79; N, 6.99; Cl, 9.35.

EXAMPLE 633-[[[1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxyamino]-3-oxo-propanoicacid, ethyl ester

According to the procedure of Example 62,1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamineis reacted with 1.1 eq of ethyl malonyl chloride in dioxane/water (1:1)in the presence of sodium acetate (2.5 eq). The crude product ispurified by column chromatography (silica gel, 3:7 acetone:hexane). Theproduct crystallizes from the chromatography solvents upon standing togive pure3-[[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxyamino]-3-oxopropanoicacid, ethyl ester (24%); mp 170°-171° C. dec.

Anal. Calcd for C₂₃ H₂₃ ClN₂ O₆ : C, 60.20; H, 5.05; N, 6.10; Cl, 7.72.Found: C, 59.80; H, 5.03; N, 5.95; Cl, 8.24.

EXAMPLE 644-[[[1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxyamino]-4-oxo-butanoicacid, methyl ester

According to the procedure of Example 62,1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamineis reacted with 2.1 eq of 3-carbomethoxypropionyl chloride indioxane/water (1:1) in the presence of sodium acetate (2.5 eq). Thecrude product is purified by column chromatography (silica gel, 1:4ethyl acetate:methylene chloride). The resulting product is slurried inethyl acetate and filtered to give pure4-[[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxyamino]-4-oxo-butanoicacid, methyl ester (24%); mp 157.5°-158° C.

Anal. Calcd for C₂₃ H₂₃ ClN₂ O₆ : C, 60.20; H, 5.05; N, 6.10; Cl, 7.72.Found: C, 60.48; H, 5.03; N, 5.98; Cl, 7.92.

EXAMPLE 654-[[[1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxyamino]-4-oxo-butanoicacid

According to the procedure of Example 62,1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamineis reacted with 1.0 eq of succinic anhydride in dioxane/water (2:1) inthe presence of sodium acetate (2.5 eq). The reaction mixture is dilutedwith ethyl acetate and is washed with dilute aqueous HCl and then withwater. The crude product is purified by recrystallization from methylenechloride. The compound is dissolved in a minimal amount of methanol,diluted with water and lyophylized to give pure4-[[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxyamino]-4-oxo-butanoicacid (44%); mp 134°-136° C.

Anal. Calcd for C₂₂ H₂₁ ClN₂ O₆.1.3H₂ O: C, 56.42; H, 4.95; N, 5.98.Found: C, 56.45; H, 4.85; N, 5.83.

EXAMPLE 66[[1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxycarbamicacid, methyl ester

According to the procedure of Example 62,1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamineis reacted with 1.1 eq of methyl chloroformate in dioxane/water (2:1) inthe presence of sodium acetate (2.5 eq). The crude product isrecrystallized from isopropyl ether:cyclohexane to give pure[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxycarbamicacid, methyl ester (63%); mp 113°-114° C.

Anal. Calcd for C₂₀ H₁₉ ClN₂ O₅ : C, 59.63; H, 4.75; N, 6.95; Cl, 8.80.Found: C, 59.74; H, 4.73; N, 6.89; Cl, 7.61.

EXAMPLE 67N-(Aminocarbonyl)-1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine

To a suspension of1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine(500 mg, 1.45 mmol) in 30 ml of 1,4-dioxane and 15 ml of water at 0° C.is added sodium isocyanate (104 mg, 1.59 mmol) followed by 1.59 ml (1.59mmol) of 1N hydrochloric acid. The reaction mixture is diluted withethyl acetate and washed once with water, and finally with a saturatedsolution of sodium chloride. It is further dried over magnesium sulfate,filtered, and concentrated in vacuo. The crude residue is recrystallizedfrom methylene chloride and dried to give 300 mg (53%) of pureN-(aminocarbonyl)-1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine(53%); mp 151.5°-154° C. dec.

Anal. Calcd for C₁₉ H₁₈ ClN₃ O₄ : C, 58.84; H, 4.68; N, 10.83; Cl, 9.14.Found: C, 58.60; H, 4.70; N, 10.72; Cl, 9.59.

EXAMPLE 681-(4-Chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-[(methylamino)carbonyl]-1H-indole-3-methanamine

According to the procedure of Example 62,1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamineis reacted with 1.1 eq of methyl isocyanate in dioxane/water (2:1) inthe absence of sodium acetate. The crude product is purified by columnchromatography (silica gel) eluting with a gradient of acetone/hexane togive pure1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-[(methylamino)carbonyl]-1H-indole-3-methanamine(51%) as an amorphous solid.

Anal. Calcd for C₂₀ H₂₀ ClN₃ O₄ : C, 59.78; H, 5.02; N, 10.46; Cl, 9.82.Found: C, 59.64; H, 5.05; N, 10.21; Cl, 9.54.

EXAMPLE 691-(4-Chlorobenzoyl)-N-[(dimethylamino)carbonyl]-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine

According to the procedure of Example 62,1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamineis reacted with 14 eq of dimethylcarbamoyl chloride and 3.5 eq of sodiumacetate (added in portions). The crude product is purified by columnchromatography (silica gel, 1:4/ethyl acetate:methylene chloride).Recrystallization from methylene chloride:hexane, followed by columnchromatography (silica gel, ether) and recrystallization frommethanol:water gives pure1-(4-chlorobenzoyl)-N-[(dimethylamino)carbonyl]-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine(30%); mp 173°-174° C.

Anal. Calcd for C₂₁ H₂₂ ClN₃ O₄ : C, 60.65; H, 5.33; N, 10.10; Cl, 8.52.Found: C, 60.90; H, 5.21; N, 9.95; Cl, 8.56.

EXAMPLE 701-(4-Chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-[(2-propenylamino)carbonyl]-1H-indole-3-methanamine

According to the procedure of Example 62,1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamineis reacted with 1.2 eq of allyl isocyanate in dioxane/water (1:1) in thepresence of sodium acetate (2.5 eq). The crude product is purified bycolumn chromatography (silica, 3:7 ethyl acetate:methylene chloride).Recrystallization from methylene chloride:hexane, and then frommethanol:water gives pure1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-[(2-propenylamino)carbonyl]-1H-indole-3-methanamine (44%); mp 148°-149° C.

Anal. Calcd for C₂₂ H₂₂ ClN₃ O₄ :

C, 61.76; H, 5.18; N, 9.82; Cl, 8.28. Found: C, 61.59; H, 5.17; N, 9.59;Cl, 8.33.

EXAMPLE 71[[[[1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol3-yl]methyl]hydroxyamino]carbonyl]carbamicacid, ethyl ester

To a solution of1-(4-chlorobenzoyl)-N-hydroxy5-methoxy-2-methyl-1H-indole-3-methanamine(540 mg, 1.57 mmol) in 30 ml of freshly distilled tetrahydrofuran at 0°C. is added dropwise 194 μl (1.88 mmol) of ethoxycarbonyl isocyanate.The reaction mixture is stirred for 10 minutes at 0° C. and concentratedin vacuo. The residue is purified by column chromatography on silicausing an ethyl acetate:methylene chloride gradient (15:85 to 1:1).Recrystallization from methylene chloride:hexane gives pure[[[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxyamino]carbonyl]carbamic acid, ethylester (68%); mp 147.5°-148° C.

Anal. Calcd for C₂₂ H₂₂ ClN₃ O₆ : C, 57.46; H, 4.82; N, 9.14; Cl, 7.71.Found: C, 57.31; H, 4.87; N, 8.99; Cl, 7.77.

EXAMPLE 72N-[[[[1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxyamino]carbonyl]glycine,ethyl ester

According to the procedure of Example 71,(1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamineis reacted with ethyl isocyanato-acetate. The crude product is purifiedby column chromatography (silica gel, 1:4 ethyl acetate:methylenechloride) to give pureN-[[[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxyamino]carbonyl]glycine,ethyl ester (27%) as an amorphous solid.

Anal. Calcd for C₂₃ H₂₄ ClN₃ O₆ : C, 58.29; H, 5.10; N, 8.87; Cl, 7.48Found: C, 58.02; H, 5.03; N, 8.74; Cl, 7.98.

EXAMPLE 731-(4-Chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-[(methylamino)thioxomethyl]-1H-indole-3-methanamine

A solution of methyl isothiocyanate (1.36 g, 18.56 mmol) in 2 ml ofdioxane is added dropwise to a suspension of1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine(2.01 g, 5.84 mmol) in 60 ml of dioxane and 60 ml of H₂ O at 0° C. Theice bath is removed. After one hour 0.5 g (6.84 mmol) additional methylisothiocyanate is added and the reaction mixture is stored in a freezerovernight. The solids are collected by filtration and recrystallizedfrom THF/hexane, rinsed with ether, and dried under high vacuum over P₂O₅ to give pure1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-[(methylamino)thioxomethyl]-1H-indole-3-methanamine(1.32 g, 54%); mp 198°-198.5° C. (dec).

Anal. Calcd for C₂₀ H₂₀ ClN₃ O₃ S: C, 57.48; H, 4.82; N, 10.05; Cl,8.48. Found: C, 57.72; H, 4.80; N, 9.67; Cl, 8.57.

EXAMPLE 74 1-(5-Methoxy-2-methyl-1H-indol-3-yl)ethanone

Dimethylacetamide (17.5 ml, 188.4 mmol) is added dropwise with stirringto phosphorous oxychloride (12.9 ml, 138.2 mmol) at 0° C. Stirring ismaintained for 45 minutes, at which time the bath is removed and5-methoxy-2-methylindole (20.25 g, 125.6 mmol) in 15 ml ofdimethylacetamide is added dropwise over a period of 75 minutes. Theresulting mixture is warmed to 40°-45° C. for 4 hours. The reactionmixture is cooled to 0° C., and 100 g of ice water is added followed bydropwise addition of a solution of sodium hydroxide (50 g) in water (75ml). The first 1/3 of this sodium hydroxide solution is added slowly andthe remainder is added quickly. The exothermic reaction is quicklywarmed to boiling for 15 minutes, cooled to room temperature andrefrigerated overnight. The resulting crystals are collected byfiltration and rinsed four times with water. Recrystallization fromethanol/water gives 17.2 g (67.2%) of pure1-(5-methoxy-2-methyl-1H-indol-3-yl)ethanone; mp 229.0°-230.5° C.

Anal. Calcd for C₁₂ H₁₃ NO₂ : C, 70.92; H, 6.45; N, 6.89. Found: C,70.92; H, 6.55; N, 6.86.

EXAMPLE 75 (5-Methoxy-2-methyl-1H-indol-3-yl)ethanone,O-(tetrahydro-2H-pyran-2-yl)oxime

To a suspension of 1-(5-methoxy-2-methyl-1H-indol-3-yl)ethanone (17.2 g,84.6 mmol) and anhydrous pyridinium hydrochloride (4.9 g, 42.3 mmol) indry pyridine (200 ml) is added dropwise a solution ofO-tetrahydropyranyl hydroxylamine (9.9 g, 84.6 mmol) in dry pyridine(200 ml) and the reaction mixture is stirred at room temperatureovernight. An additional 3.0 g (25.6 mmol) of O-tetrahydropyranylhydroxylamine is added and the reaction mixture is stirred at roomtemperature overnight. It is concentrated in vacuo to about 1/4 volume,diluted with ethyl acetate and washed four times with water and oncewith a saturated solution of sodium chloride. The organic layer is driedover magnesium sulfate, filtered, and slowly concentrated in vacuo togive a total of 23.3 g (91.5%) (from three crops) of crystalline(5-methoxy-2-methyl-1H-indol-3-yl)ethanone,0-(tetrahydro-2H-pyran-2-yl)oxime; mp 156.5°-157.5° C.

Anal. Calcd for C₁₇ H₂₂ N₂ O₃ : C, 67.53; H, 7.33; N, 9.26. Found: C,67.55; H, 7.44; N, 9.26.

EXAMPLE 761-(4-Chlorobenzoyl)-5-methoxy-2-methyl-3-[1-[[(tetrahydro-2H-pyran-2-yl)oxy]imino]ethyl]-1H-indole

To a solution of (5-methoxy-2-methyl-1H-indol-3-yl)ethanone,O-(tetrahydro-2H-pyran-2-yl)oxime (23.3 g, 77.3 mmol) in drydimethylformamide (500 ml) is added oil free sodium hydride (2.0 g, 83.3mmol). The reaction mixture is stirred for four hours at ambienttemperature. It is cooled to 0° C. and freshly distilled 4-chlorobenzoylchloride is added dropwise over 15 minutes. The reaction mixture isstirred for an additional hour, at which time it is diluted with ethylacetate and water and the aqueous layer acidified to pH=3 with 1Nhydrochloric acid. The organic layer is washed four additional timeswith large volumes of water. The organic phase is dried by washing witha saturated solution of sodium chloride and then over magnesium sulfate.It is filtered and concentrated in vacuo to an amorphous solid which isrecrystallized from hot isopropyl ether to give 26.9 g (79.1%) of1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-[1-[[(tetrahydro-2H-pyran-2-yl)oxy]imino]ethyl]-1H-indole;mp 115°-119° C.

Anal. Calcd for C₂₄ H₂₅ ClN₂ O₄ : C, 65.38; H, 5.71; Cl, 8.04; N, 6.35;Found: C, 65.06; H, 5.61; Cl, 8.34; N, 5.95.

EXAMPLE 771-(4-Chlorobenzoyl)-3-[1-(hydroxyimino)ethyl]-5-methoxy-2-methyl-1H-indole

To a solution of1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-[1-[[(tetrahydro-2H-pyran-2-yl)oxy]imino]ethyl]-1H-indole(5.0 g, 11.3 mmol) in tetrahydrofuran (115 ml) is added 10 ml ofconcentrated hydrochloric acid. The reaction mixture is stirred for 21/2hours, at which time it is neutralized with concentrated ammoniumhydroxide. It is concentrated to near dryness, diluted with ethylacetate and washed twice with water and once with a saturated solutionof sodium chloride. The organic phase is further dried over magnesiumsulfate, filtered, and concentrated slowly in vacuo to 50 ml. Thepowdery crystals are collected to give 2.8 g (70.4%) of pure1-(4-chlorobenzoyl)-3-[1-(hydroxyimino)ethyl]-5-methoxy-2-methyl-1H-indole;mp darkens (chars) at 170°-197° C. (dec).

Anal. Calcd for C₁₉ H₁₇ ClN₂ O₃ : C, 63.96; H, 4.80; Cl, 9.94; N, 7.85.Found: C, 63.71; H, 4.82; Cl, 10.06; N, 7.64.

EXAMPLE 781-(4-Chlorobenzoyl)-3-[1-(hydroxyamino)ethyl]-5-methoxy-2-methyl-1H-indole

To a solution of1-(4-chlorobenzoyl)-3-[1-(hydroxyamino)ethyl]-5-methoxy-2-methyl-1H-indole(1.0 g, 2.80 mmol) in acetic acid (30 ml) is added methyl orangeindicator and three drops of concentrated hydrochloric acid. Eightportions of 300 mg (4.80 mmol) of sodium cyanoborohydride is added every30 minutes. The reaction mixture is diluted with 50 ml of ethyl acetateand 25 ml of methylene chloride, cooled to 0°, and quenched with 500 mlof a saturated solution of sodium bicarbonate added dropwise. It is thenfurther diluted with 500 ml of ethyl acetate, and the phases areseparated. The organic layer is extracted again with a saturatedsolution of sodium bicarbonate, once with water, and once with asaturated solution of sodium chloride. It is further dried overmagnesium sulfate, filtered, and concentrated in vacuo to 2 ml. Theaddition of 2 ml of methylene chloride precipitates 500 mg of startingoxime. The mother liquor is concentrated to crude 1-(4-chlorobenzoyl)-3-[1-(hydroxyamino)ethyl]-5-methoxy-2-methyl-1H-indoleas a yellow oil which is used without further purification in thesubsequent reaction. A sample recrystallized from methylene chloride hasa mp of 179°-180° C. (dec).

Anal. Calcd for C₁₉ H₁₉ ClN₂ O₃ : C, 63.60; H, 5.34; N, 7.81. Found: C,61.85; H, 5.22; N, 7.61.

EXAMPLE 79N-[1-[1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]ethyl]-N-hydroxyacetamide

To a solution of 500 mg of1-(4-chlorobenzoyl)-3-[1-(hydroxyamino)ethyl]-5-methoxy-2-methyl-1H-indole(crude product of Example 78) and 230 mg (2.8 mmol) of sodium acetate in20 ml of 1,4-dioxane and 5 ml of water is added dropwise 90 μl (1.26mmol) of acetyl chloride. The reaction mixture is stirred for 10minutes, at which time it is diluted with ethyl acetate and washed twicewith water and once with a saturated solution of sodium chloride. Theorganic phase is further dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue is purified by column chromatography,eluting with a gradient of ethyl acetate:methylene chloride (3:7 to1:1). A second chromatography (silica gel, ether), and finallyrecrystallization from methanol gives 71 mg (6.3% from oxime) of pureN-[1-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]ethyl]-N-hydroxyacetamide;mp softens at 90° C. then decomposes as the temperature increases.

Anal. Calcd for C₂₁ H₂₁ ClN₂ O₄ : C, 62.92; H, 5.28; N, 6.99; Cl, 8.84Found: C, 63.26; H, 5.37; N, 6.64; Cl, 9.35.

We claim:
 1. A compound of the formula (I) ##STR40## and apharmaceutically acceptable acid addition or base salt thereof; whereinAr is (1) ##STR41## wherein R₁, R₂, and R₃ are independently hydrogen,fluoro, chloro, bromo, iodo, CF₃, lower alkyl, CN, hydroxy, loweralkoxy, --S(O)q-lower alkyl wherein q is an integer of 0, 1, or 2, NO₂or NR₄ R₅ wherein R₄ or R₅ are independently hydrogen, lower alkyl,lower acyl; ##STR42## Y is O or S; W is lower alkyl, aryl, aralkyl,lower alkoxy, NR₆ R₇, (CH₂)_(n) CO₂ R₇, NH(CH₂)_(m) CO₂ R₇, NH(CH₂)_(p)NR₆ R₇, or NHCH₂ CH═CH₂ wherein R₅ is independently as defined above, R₆and R₇ are independently hydrogen or lower alkyl, n is an integer offrom 0 to 3, m is an integer of from 0 to 3; and p is an integer of 2 or3; with the proviso that Y cannot be sulfur when n is
 0. 2. A compoundof claim 1 wherein X is CH₂, ##STR43##
 3. A compound of claim 1 whereinX is CH═CHCH₂ or ##STR44##
 4. A compound of claim 1 wherein Y is oxygen.5. A compound of claim 1 wherein Y is sulfur.
 6. A compound of claim 1wherein Ar is ##STR45## wherein R₁, R₂, R₃, X, Y and W are as definedabove.
 7. A compound of claim 1 wherein Ar is ##STR46## wherein X, Y andW are as defined above.
 8. A compound of claim 6 which isN-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methyl]-N-hydroxyacetamide.9. The monosodium salt of claim
 8. 10. The compound of claim 6 which isN-hydroxy-N-[[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]methyl]acetamide.11. The monosodium salt of claim
 10. 12. A compound of claim 6 which isN-hydroxy-N-[[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]methyl]carbamicacid, ethyl ester.
 13. A compound of claim 6 which isN-hydroxy-N'-methyl-N-[[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]methyl]urea.14. A compound of claim 6 whichisN-[[2-[(2,3-dimethyphenyl)amino]phenyl]methyl]-N-hydroxyacetamide,N-[[2-[(2,6-dichlorophenyl)amino]phenyl]methyl]-N-hydroxyacetamide,N-[1-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]ethyl]-N-hydroxyacetamide.15. A compound of claim 7 which is[(9H-fluoren-2-ylmethyl)hydroxyamino]oxoaceticacid,N-(9H-fluoren-2-ylmethyl)-N-hydroxyacetamide,[(9H-fluoren-2-ylmethyl)hydroxyamino]oxoacetic acid, ethyl ester,N-(9H-fluoren-2-ylmethyl)-N-hydroxy-2-methylpropanamide,N-(9H-fluoren-2-ylmethyl)-N-hydroxy-N'-methylurea,N-[1-(9H-fluoren-2-yl)ethyl]-N-hydroxy-N'-methylurea,N'-ethyl-N-[1-(9H-fluoren-2-yl)ethyl]-N-hydroxyurea,N-(1-(9H-fluoren-2-yl)ethyl-N-hydroxy-N'-methylthiourea,N-(1-(9H-fluoren-2-yl)ethyl-N-hydroxyacetamide,N-(1-(9H-fluoren-2-yl)ethyl)-N-hydroxy-2-methylpropanamide, orN-(1-(9H-fluoren-2-yl)ethyl)-N-hydroxy-N'-ethylthiourea.
 16. A compoundwhich is N-hydroxy-9H-fluoren-2-methanamine.
 17. A compound which isN-hydroxy-α-methyl-9H-fluorene-2-methanamine.
 18. A pharmaceuticalcomposition for use as an antiinflammatory agent comprising anantiinflammatory effective amount of the compound of claim 1 and apharmaceutical carrier.
 19. A method of treating inflammation in amammal suffering therefrom which comprises administering atherapeutically effective amount of the compound of claim 1 in unitdosage form.
 20. A pharmaceutical composition comprising atherapeutically effective amount of the compound of claim 1 additionallycomprising an effective amount of a second active ingredient that is anonsteroidal antiinflammatory drug; a peripheral analgesic agent; acyclooxygenase inhibitor; a leukotriene antagonist; an antihistaminicagent; a prostaglandin antagonist or a thromboxane antagonist.
 21. Apharmaceutical composition for use as an antiinflammatory agentcomprising an antiinflammatory effective amount of the compound of claim16 and a pharmaceutical carrier.
 22. A method of treating inflammationin a mammal suffering therefrom which comprises administering atherapeutically effective amount of the compound of claim 17 in unitdosage form.